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Sample records for clinical prion disease

  1. Prion disease induced alterations in gene expression in spleen and brain prior to clinical symptoms

    Directory of Open Access Journals (Sweden)

    Hyeon O Kim

    2008-09-01

    Full Text Available Hyeon O Kim1, Greg P Snyder1, Tyler M Blazey1, Richard E Race2, Bruce Chesebro2, Pamela J Skinner11Department of Veterinary and Biomedical Sciences, University of Minnesota, USA; 2NIH Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, Hamilton, Montana, USAAbstract: Prion diseases are fatal neurodegenerative disorders that affect animals and humans. There is a need to gain understanding of prion disease pathogenesis and to develop diagnostic assays to detect prion diseases prior to the onset of clinical symptoms. The goal of this study was to identify genes that show altered expression early in the disease process in the spleen and brain of prion disease-infected mice. Using Affymetrix microarrays, we identified 67 genes that showed increased expression in the brains of prion disease-infected mice prior to the onset of clinical symptoms. These genes function in many cellular processes including immunity, the endosome/lysosome system, hormone activity, and the cytoskeleton. We confirmed a subset of these gene expression alterations using other methods and determined the time course in which these changes occur. We also identified 14 genes showing altered expression prior to the onset of clinical symptoms in spleens of prion disease infected mice. Interestingly, four genes, Atp1b1, Gh, Anp32a, and Grn, were altered at the very early time of 46 days post-infection. These gene expression alterations provide insights into the molecular mechanisms underlying prion disease pathogenesis and may serve as surrogate markers for the early detection and diagnosis of prion disease.Keywords: prion disease, microarrays, gene expression

  2. The genetics of prion diseases.

    Science.gov (United States)

    Mastrianni, James A

    2010-04-01

    Prion diseases are a rare group of fatal neurodegenerative disorders of humans and animals that manifest primarily as progressive dementia and ataxia. Unique to these diseases is the prion, a misfolded isoform of the prion protein that can transmit disease from cell to cell or host to host by associating with, and transforming, normal prion protein into the misfolded isoform (the pathogenic scrapie-inducing form). Although the majority of cases occur on a sporadic basis, and rarely result from exposure to prions, such as mad cow disease, 10-15% are attributable to the presence of an autosomal dominant mutation of the prion protein gene (PRNP). Single base pair changes, or the insertion of one or more multiples of a 24 base pair repeat segment, make up the known sequence alterations of PRNP associated with genetic prion disease. The common polymorphic codon 129 of PRNP also plays an important and complex role in risk and phenotype of sporadic and genetic prion disease. This review will focus on the clinical and histopathologic features of the genetic prion diseases. Selected mutations will be highlighted as a way to illustrate general phenotype-genotype correlations. PMID:20216075

  3. Continuous intraventricular infusion of pentosan polysulfate: clinical trial against prion diseases.

    Science.gov (United States)

    Tsuboi, Yoshio; Doh-Ura, Katsumi; Yamada, Tatsuo

    2009-10-01

    Prion diseases are progressive neurological disorders due to abnormal prion protein (PrP(Sc)) deposition in the central nervous system. At present, there is no effective treatment available for any form of prion disease. Pentosan polysulfate (PPS) has been shown to prolong significantly the incubation period in mice with PrP(Sc) infection when administered to the cerebral ventricles in preclinical trials. In human studies conducted in European countries and Japan, intraventricular PPS was administered to patients with different forms of prion disease and was well tolerated. We report 11 patients with prion disease treated with intraventricular PPS at Fukuoka University from 2004. Cases included three familial CJD (two with V180I mutation, one GSS with P102L mutation), two iatrogenic CJD, and six sporadic CJD cases. At present, average survival period after treatment was 24.2 months (range, 4-49). Seven cases died of sepsis and pneumonia. Subdural effusion with various degrees was seen on CT scan in most cases. Except for these, adverse effects did not occur in the treatment period. Although our preliminary study of the new treatment with PPS by continuous intraventricular infusion showed no apparent improvement of clinical features in patients with prion disease, the possibility of extended survival in some patients receiving long-term PPS was suggested.

  4. Prion diseases of the brain

    International Nuclear Information System (INIS)

    The prion diseases of the brain, especially Creutzfeldt-Jakob disease, are rare fatal neurodegenerative disorders. A definitive CJD diagnosis is currently only possible by a brain biopsy or post mortem autopsy. The diagnosis of Creutzfeldt-Jakob disease is based on clinical signs, pathognomonic EEG, on typical MRI findings and the examination of the cerebrospinal fluid. Using the MRI the diagnosis Creutzfeldt-Jakob disease can be confirmed or excluded with high certainty. The MRI examination should contain diffusion-weighted and FLAIR imaging sequences. This review article provides an overview of the prion diseases of the brain with the corresponding imaging findings.

  5. An overview of animal prion diseases.

    Science.gov (United States)

    Imran, Muhammad; Mahmood, Saqib

    2011-01-01

    Prion diseases are transmissible neurodegenerative conditions affecting human and a wide range of animal species. The pathogenesis of prion diseases is associated with the accumulation of aggregates of misfolded conformers of host-encoded cellular prion protein (PrPC). Animal prion diseases include scrapie of sheep and goats, bovine spongiform encephalopathy (BSE) or mad cow disease, transmissible mink encephalopathy, feline spongiform encephalopathy, exotic ungulate spongiform encephalopathy, chronic wasting disease of cervids and spongiform encephalopathy of primates. Although some cases of sporadic atypical scrapie and BSE have also been reported, animal prion diseases have basically occurred via the acquisition of infection from contaminated feed or via the exposure to contaminated environment. Scrapie and chronic wasting disease are naturally sustaining epidemics. The transmission of BSE to human has caused more than 200 cases of variant Cruetzfeldt-Jacob disease and has raised serious public health concerns. The present review discusses the epidemiology, clinical neuropathology, transmissibility and genetics of animal prion diseases. PMID:22044871

  6. Prions and prion diseases: fundamentals and mechanistic details.

    Science.gov (United States)

    Ryou, Chongsuk

    2007-07-01

    Prion diseases, often called transmissible spongiform encephalopathies (TSEs), are infectious diseases that accompany neurological dysfunctions in many mammalian hosts. Prion diseases include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE, "mad cow disease") in cattle, scrapie in sheep, and chronic wasting disease (CWD) in deer and elks. The cause of these fatal diseases is a proteinaceous pathogen termed prion that lacks functional nucleic acids. As demonstrated in the BSE outbreak and its transmission to humans, the onset of disease is not limited to a certain species but can be transmissible from one host species to another. Such a striking nature ofprions has generated huge concerns in public health and attracted serious attention in the scientific communities. To date, the potential transmission ofprions to humans via foodbome infectiorn and iatrogenic routes has not been alleviated. Rather, the possible transmission of human to human or cervids to human aggravates the terrifying situation across the globe. In this review, basic features about prion diseases including clinical and pathological characteristics, etiology, and transmission of diseases are described. Based on recently accumulated evidences, the molecular and biochemical aspects of prions, with an emphasis on the molecular interactions involved in prion conversion that is critical during prion replication and pathogenesis, are also addressed. PMID:18051314

  7. Genetics Home Reference: prion disease

    Science.gov (United States)

    ... as bovine spongiform encephalopathy (BSE) or, more commonly, "mad cow disease." Another example of an acquired human prion disease ... forms of prion disease , including kuru and variant Creutzfeldt-Jakob disease, are not inherited. Related Information What does it ...

  8. Prion diseases: immunotargets and therapy

    Science.gov (United States)

    Burchell, Jennifer T; Panegyres, Peter K

    2016-01-01

    Transmissible spongiform encephathalopathies or prion diseases are a group of neurological disorders characterized by neuronal loss, spongiform degeneration, and activation of astrocytes or microglia. These diseases affect humans and animals with an extremely high prevalence in some species such as deer and elk in North America. Although rare in humans, they result in a devastatingly swift neurological progression with dementia and ataxia. Patients usually die within a year of diagnosis. Prion diseases are familial, sporadic, iatrogenic, or transmissible. Human prion diseases include Kuru, sporadic, iatrogenic, and familial forms of Creutzfeldt–Jakob disease, variant Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia. The causative agent is a misfolded version of the physiological prion protein called PrPSc in the brain. There are a number of therapeutic options currently under investigation. A number of small molecules have had some success in delaying disease progression in animal models and mixed results in clinical trials, including pentosan polysulfate, quinacrine, and amphotericin B. More promisingly, immunotherapy has reported success in vitro and in vivo in animal studies and clinical trials. The three main branches of immunotherapy research are focus on antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific CD4+ T-lymphocytes. Vaccines utilizing antibodies generally target disease-specific epitopes that are only exposed in the misfolded PrPSc conformation. Vaccines utilizing antigen-loaded dendritic cell have the ability to bypass immune tolerance and prime CD4+ cells to initiate an immune response. Adoptive transfer of CD4+ T-cells is another promising target as this cell type can orchestrate the adaptive immune response. Although more research into mechanisms and safety is required, these immunotherapies offer novel therapeutic targets for prion

  9. Prion diseases: immunotargets and therapy.

    Science.gov (United States)

    Burchell, Jennifer T; Panegyres, Peter K

    2016-01-01

    Transmissible spongiform encephathalopathies or prion diseases are a group of neurological disorders characterized by neuronal loss, spongiform degeneration, and activation of astrocytes or microglia. These diseases affect humans and animals with an extremely high prevalence in some species such as deer and elk in North America. Although rare in humans, they result in a devastatingly swift neurological progression with dementia and ataxia. Patients usually die within a year of diagnosis. Prion diseases are familial, sporadic, iatrogenic, or transmissible. Human prion diseases include Kuru, sporadic, iatrogenic, and familial forms of Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. The causative agent is a misfolded version of the physiological prion protein called PrP(Sc) in the brain. There are a number of therapeutic options currently under investigation. A number of small molecules have had some success in delaying disease progression in animal models and mixed results in clinical trials, including pentosan polysulfate, quinacrine, and amphotericin B. More promisingly, immunotherapy has reported success in vitro and in vivo in animal studies and clinical trials. The three main branches of immunotherapy research are focus on antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific CD4(+) T-lymphocytes. Vaccines utilizing antibodies generally target disease-specific epitopes that are only exposed in the misfolded PrP(Sc) conformation. Vaccines utilizing antigen-loaded dendritic cell have the ability to bypass immune tolerance and prime CD4(+) cells to initiate an immune response. Adoptive transfer of CD4(+) T-cells is another promising target as this cell type can orchestrate the adaptive immune response. Although more research into mechanisms and safety is required, these immunotherapies offer novel therapeutic targets for prion

  10. Nanoimaging for prion related diseases.

    Science.gov (United States)

    Krasnoslobodtsev, Alexey V; Portillo, Alexander M; Deckert-Gaudig, Tanja; Deckert, Volker; Lyubchenko, Yuri L

    2010-01-01

    Misfolding and aggregation of prion proteins is linked to a number of neurodegenerative disorders such as Creutzfeldt-Jacob disease (CJD) and its variants: Kuru, Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia. In prion diseases, infectious particles are proteins that propagate by transmitting a misfolded state of a protein, leading to the formation of aggregates and ultimately to neurodegeneration. Prion phenomenon is not restricted to humans. There are a number of prion-related diseases in a variety of mammals, including bovine spongiform encephalopathy (BSE, also known as "mad cow disease") in cattle. All known prion diseases, collectively called transmissible spongiform encephalopathies (TSEs), are untreatable and fatal. Prion proteins were also found in some fungi where they are responsible for heritable traits. Prion proteins in fungi are easily accessible and provide a powerful model for understanding the general principles of prion phenomenon and molecular mechanisms of mammalian prion diseases. Presently, several fundamental questions related to prions remain unanswered. For example, it is not clear how prions cause the disease. Other unknowns include the nature and structure of infectious agent and how prions replicate. Generally, the phenomenon of misfolding of the prion protein into infectious conformations that have the ability to propagate their properties via aggregation is of significant interest. Despite the crucial importance of misfolding and aggregation, very little is currently known about the molecular mechanisms of these processes. While there is an apparent critical need to study molecular mechanisms underlying misfolding and aggregation, the detailed characterization of these single molecule processes is hindered by the limitation of conventional methods. Although some issues remain unresolved, much progress has been recently made primarily due to the application of nanoimaging tools. The use of nanoimaging methods shows

  11. Prion diseases: immunotargets and therapy

    Directory of Open Access Journals (Sweden)

    Burchell JT

    2016-06-01

    Full Text Available Jennifer T Burchell, Peter K Panegyres Neurodegenerative Disorders Research Pty Ltd, West Perth, Western Australia, Australia Abstract: Transmissible spongiform encephathalopathies or prion diseases are a group of neurological disorders characterized by neuronal loss, spongiform degeneration, and activation of astrocytes or microglia. These diseases affect humans and animals with an extremely high prevalence in some species such as deer and elk in North America. Although rare in humans, they result in a devastatingly swift neurological progression with dementia and ataxia. Patients usually die within a year of diagnosis. Prion diseases are familial, sporadic, iatrogenic, or transmissible. Human prion diseases include Kuru, sporadic, iatrogenic, and familial forms of Creutzfeldt–Jakob disease, variant Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia. The causative agent is a misfolded version of the physiological prion protein called PrPSc in the brain. There are a number of therapeutic options currently under investigation. A number of small molecules have had some success in delaying disease progression in animal models and mixed results in clinical trials, including pentosan polysulfate, quinacrine, and amphotericin B. More promisingly, immunotherapy has reported success in vitro and in vivo in animal studies and clinical trials. The three main branches of immunotherapy research are focus on antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific CD4+ T-lymphocytes. Vaccines utilizing antibodies generally target disease-specific epitopes that are only exposed in the misfolded PrPSc conformation. Vaccines utilizing antigen-loaded dendritic cell have the ability to bypass immune tolerance and prime CD4+ cells to initiate an immune response. Adoptive transfer of CD4+ T-cells is another promising target as this cell type can orchestrate the

  12. The immunobiology of prion diseases.

    Science.gov (United States)

    Aguzzi, Adriano; Nuvolone, Mario; Zhu, Caihong

    2013-12-01

    Individuals infected with prions succumb to brain damage, and prion infections continue to be inexorably lethal. However, many crucial steps in prion pathogenesis occur in lymphatic organs and precede invasion of the central nervous system. In the past two decades, a great deal has been learnt concerning the cellular and molecular mechanisms of prion lymphoinvasion. These properties are diagnostically useful and have, for example, facilitated preclinical diagnosis of variant Creutzfeldt-Jakob disease in the tonsils. Moreover, the early colonization of lymphoid organs can be exploited for post-exposure prophylaxis of prion infections. As stromal cells of lymphoid organs are crucial for peripheral prion infection, the dedifferentiation of these cells offers a powerful means of hindering prion spread in infected individuals. In this Review, we discuss the current knowledge of the immunobiology of prions with an emphasis on how basic discoveries might enable translational strategies. PMID:24189576

  13. An overview of animal prion diseases

    Directory of Open Access Journals (Sweden)

    Imran Muhammad

    2011-11-01

    Full Text Available Abstract Prion diseases are transmissible neurodegenerative conditions affecting human and a wide range of animal species. The pathogenesis of prion diseases is associated with the accumulation of aggregates of misfolded conformers of host-encoded cellular prion protein (PrPC. Animal prion diseases include scrapie of sheep and goats, bovine spongiform encephalopathy (BSE or mad cow disease, transmissible mink encephalopathy, feline spongiform encephalopathy, exotic ungulate spongiform encephalopathy, chronic wasting disease of cervids and spongiform encephalopathy of primates. Although some cases of sporadic atypical scrapie and BSE have also been reported, animal prion diseases have basically occurred via the acquisition of infection from contaminated feed or via the exposure to contaminated environment. Scrapie and chronic wasting disease are naturally sustaining epidemics. The transmission of BSE to human has caused more than 200 cases of variant Cruetzfeldt-Jacob disease and has raised serious public health concerns. The present review discusses the epidemiology, clinical neuropathology, transmissibility and genetics of animal prion diseases.

  14. Prion and prion-like diseases in animals.

    Science.gov (United States)

    Aguilar-Calvo, Patricia; García, Consolación; Espinosa, Juan Carlos; Andreoletti, Olivier; Torres, Juan María

    2015-09-01

    Transmissible spongiform encephalopaties (TSEs) are fatal neurodegenerative diseases characterized by the aggregation and accumulation of the misfolded prion protein in the brain. Other proteins such as β-amyloid, tau or Serum Amyloid-A (SAA) seem to share with prions some aspects of their pathogenic mechanism; causing a variety of so called prion-like diseases in humans and/or animals such as Alzheimer's, Parkinson's, Huntington's, Type II diabetes mellitus or amyloidosis. The question remains whether these misfolding proteins have the ability to self-propagate and transmit in a similar manner to prions. In this review, we describe the prion and prion-like diseases affecting animals as well as the recent findings suggesting the prion-like transmissibility of certain non-prion proteins.

  15. Prions

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    W. Bodemer

    2016-09-01

    BSE is always unknown. Telemetry revealed a shift in sleep–wake cycles early on, long before behavioral changes or clinical symptoms appeared. Pathology confirmed non-neuronal tissue as hidden places where prions exist. The rhesus model also allowed first comparative studies of epigenetic modifications on RNA in peripheral blood and brain tissue collected from uninfected and prion-infected animals. To conclude, our studies clearly demonstrated that this model is valid since progression to disease is almost identical to human CJD.

  16. Infectious prions in pre-clinical deer and transmission of chronic wasting disease solely by environmental exposure.

    Directory of Open Access Journals (Sweden)

    Candace K Mathiason

    Full Text Available Key to understanding the epidemiology and pathogenesis of prion diseases, including chronic wasting disease (CWD of cervids, is determining the mode of transmission from one individual to another. We have previously reported that saliva and blood from CWD-infected deer contain sufficient infectious prions to transmit disease upon passage into naïve deer. Here we again use bioassays in deer to show that blood and saliva of pre-symptomatic deer contain infectious prions capable of infecting naïve deer and that naïve deer exposed only to environmental fomites from the suites of CWD-infected deer acquired CWD infection after a period of 15 months post initial exposure. These results help to further explain the basis for the facile transmission of CWD, highlight the complexities associated with CWD transmission among cervids in their natural environment, emphasize the potential utility of blood-based testing to detect pre-clinical CWD infection, and could augur similar transmission dynamics in other prion infections.

  17. Human prion diseases: surgical lessons learned from iatrogenic prion transmission.

    Science.gov (United States)

    Bonda, David J; Manjila, Sunil; Mehndiratta, Prachi; Khan, Fahd; Miller, Benjamin R; Onwuzulike, Kaine; Puoti, Gianfranco; Cohen, Mark L; Schonberger, Lawrence B; Cali, Ignazio

    2016-07-01

    The human prion diseases, or transmissible spongiform encephalopathies, have captivated our imaginations since their discovery in the Fore linguistic group in Papua New Guinea in the 1950s. The mysterious and poorly understood "infectious protein" has become somewhat of a household name in many regions across the globe. From bovine spongiform encephalopathy (BSE), commonly identified as mad cow disease, to endocannibalism, media outlets have capitalized on these devastatingly fatal neurological conditions. Interestingly, since their discovery, there have been more than 492 incidents of iatrogenic transmission of prion diseases, largely resulting from prion-contaminated growth hormone and dura mater grafts. Although fewer than 9 cases of probable iatrogenic neurosurgical cases of Creutzfeldt-Jakob disease (CJD) have been reported worldwide, the likelihood of some missed cases and the potential for prion transmission by neurosurgery create considerable concern. Laboratory studies indicate that standard decontamination and sterilization procedures may be insufficient to completely remove infectivity from prion-contaminated instruments. In this unfortunate event, the instruments may transmit the prion disease to others. Much caution therefore should be taken in the absence of strong evidence against the presence of a prion disease in a neurosurgical patient. While the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have devised risk assessment and decontamination protocols for the prevention of iatrogenic transmission of the prion diseases, incidents of possible exposure to prions have unfortunately occurred in the United States. In this article, the authors outline the historical discoveries that led from kuru to the identification and isolation of the pathological prion proteins in addition to providing a brief description of human prion diseases and iatrogenic forms of CJD, a brief history of prion disease nosocomial transmission

  18. [Molecular bases of prion diseases].

    Science.gov (United States)

    Pokrovskiĭ, V I; Kiselev, O I

    1998-01-01

    The paper briefly analyzes the origin of priones and their association with the cellular gene and homologous protein of diseases in man and animals. There is evidence for a direct relationship of the agents that cause spongious encephalitis in the cattle and a new type of Creutzfeldt-Jacob disease in man. The molecular organization of priones and the conformational cellular protein changes underlying the infectious activation of the cell homologue of priones. Emphasis is first laid on the capacity of the cell homologue of priones and their infectiously active derivative to bind to DNA or RNA. In the context of concepts of the priones yeasts an attempt was made to explain the reproduction through the altered control of translation of mRNA that encodes the cellular homologue of priones, which accounts for the duration of the incubation period of the disease. The infections caused by priones are referred to as the so-called slow infections. But in the context of the proposed hypothesis, an infective process in the tissues did not really have some typical signs of infection and resembles accumulation diseases more without the replicative burst typical of infectious processes. The paper gives data on the vital cycle of priones in infected animals and changes in the accumulation of an infective agent. This assesses the currently available diagnostic methods and gives preference to the methods which will be based on the use of monoclonal antibodies that specifically recognize the conformationally altered form of an infectious prione or on the identification of primary oligomeric forms which manifest the onset of amyloidization of the damaged tissues. The main conclusion of the paper is that protein prionization is a common biological phenomenon and the diseases caused by these processes will increase in number in the near future, which makes it necessary to develop diagnostic methods and universal treatments of diseases, such as bacterial infections by using antibiotics.

  19. Statistical Mechanics of Prion Diseases

    International Nuclear Information System (INIS)

    We present a two-dimensional, lattice based, protein-level statistical mechanical model for prion diseases (e.g., mad cow disease) with concomitant prion protein misfolding and aggregation. Our studies lead us to the hypothesis that the observed broad incubation time distribution in epidemiological data reflect fluctuation dominated growth seeded by a few nanometer scale aggregates, while much narrower incubation time distributions for innoculated lab animals arise from statistical self-averaging. We model ''species barriers'' to prion infection and assess a related treatment protocol

  20. Statistical Mechanics of Prion Diseases

    Energy Technology Data Exchange (ETDEWEB)

    Slepoy, A.; Singh, R. R. P.; Pazmandi, F.; Kulkarni, R. V.; Cox, D. L.

    2001-07-30

    We present a two-dimensional, lattice based, protein-level statistical mechanical model for prion diseases (e.g., mad cow disease) with concomitant prion protein misfolding and aggregation. Our studies lead us to the hypothesis that the observed broad incubation time distribution in epidemiological data reflect fluctuation dominated growth seeded by a few nanometer scale aggregates, while much narrower incubation time distributions for innoculated lab animals arise from statistical self-averaging. We model ''species barriers'' to prion infection and assess a related treatment protocol.

  1. Evidence for oxidative damage to prion protein in prion diseases

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    In prion diseases the irreversible protein structural transformation process is completed in the brains of mammals within a few months, the uniformly generated infectivity displays extraordinary resistance to inactivation, suggesting that a vital energy source is required for the production of infectious particles. Considering the high oxygen-respiration rate in the brains, prion protein oxidative damage can be the crucial factor. Both theoretical consideration of the nature of protein radical reactions and a large body of previously unraveled feature of scrapie and prion diseases have provided multiple distinct lines of compelling evidence which persuasively support a suggestion that the infectious agents may be prion (free) radicals produced from protein oxidative damage. This paper describes that scrapie prions are most likely formed from prion radicals and oxidative species-mediated sequence-specific cross-linking of benign prion proteins.

  2. Conformational conversion of prion protein in prion diseases

    Institute of Scientific and Technical Information of China (English)

    Zheng Zhou; Gengfu Xiao

    2013-01-01

    Prion diseases are a group of infectious fatal neurodegenerative diseases.The conformational conversion of a cellular prion protein (PrPC) into an abnormal misfolded isoform (PrPSc) is the key event in prion diseases pathology.Under normal conditions,the high-energy barrier separates PrPC from PrPsc isoform.However,pathogenic mutations,modifications as well as some cofactors,such as glycosaminoglycans,nucleic acids,and lipids,could modulate the conformationai conversion process.Understanding the mechanism of conformational conversion of prion protein is essential for the biomedical research and the treatment of prion diseases.Particularly,the characterization of cofactors interacting with prion protein might provide new diagnostic and therapeutic strategies.

  3. An overview of animal prion diseases

    OpenAIRE

    Imran Muhammad; Mahmood Saqib

    2011-01-01

    Abstract Prion diseases are transmissible neurodegenerative conditions affecting human and a wide range of animal species. The pathogenesis of prion diseases is associated with the accumulation of aggregates of misfolded conformers of host-encoded cellular prion protein (PrPC). Animal prion diseases include scrapie of sheep and goats, bovine spongiform encephalopathy (BSE) or mad cow disease, transmissible mink encephalopathy, feline spongiform encephalopathy, exotic ungulate spongiform encep...

  4. Prion Diseases as Transmissible Zoonotic Diseases

    OpenAIRE

    Lee, Jeongmin; Kim, Su Yeon; Hwang, Kyu Jam; Ju, Young Ran; Woo, Hee-Jong

    2013-01-01

    Prion diseases, also called transmissible spongiform encephalopathies (TSEs), lead to neurological dysfunction in animals and are fatal. Infectious prion proteins are causative agents of many mammalian TSEs, including scrapie (in sheep), chronic wasting disease (in deer and elk), bovine spongiform encephalopathy (BSE; in cattle), and Creutzfeldt–Jakob disease (CJD; in humans). BSE, better known as mad cow disease, is among the many recently discovered zoonotic diseases. BSE cases were first r...

  5. Prion diseases as transmissible zoonotic diseases.

    Science.gov (United States)

    Lee, Jeongmin; Kim, Su Yeon; Hwang, Kyu Jam; Ju, Young Ran; Woo, Hee-Jong

    2013-02-01

    Prion diseases, also called transmissible spongiform encephalopathies (TSEs), lead to neurological dysfunction in animals and are fatal. Infectious prion proteins are causative agents of many mammalian TSEs, including scrapie (in sheep), chronic wasting disease (in deer and elk), bovine spongiform encephalopathy (BSE; in cattle), and Creutzfeldt-Jakob disease (CJD; in humans). BSE, better known as mad cow disease, is among the many recently discovered zoonotic diseases. BSE cases were first reported in the United Kingdom in 1986. Variant CJD (vCJD) is a disease that was first detected in 1996, which affects humans and is linked to the BSE epidemic in cattle. vCJD is presumed to be caused by consumption of contaminated meat and other food products derived from affected cattle. The BSE epidemic peaked in 1992 and decreased thereafter; this decline is continuing sharply owing to intensive surveillance and screening programs in the Western world. However, there are still new outbreaks and/or progression of prion diseases, including atypical BSE, and iatrogenic CJD and vCJD via organ transplantation and blood transfusion. This paper summarizes studies on prions, particularly on prion molecular mechanisms, BSE, vCJD, and diagnostic procedures. Risk perception and communication policies of the European Union for the prevention of prion diseases are also addressed to provide recommendations for appropriate government policies in Korea. PMID:24159531

  6. A novel mutation (G114V) in the prion protein gene in a family with inherited prion disease.

    Science.gov (United States)

    Rodriguez, M-M; Peoc'h, K; Haïk, S; Bouchet, C; Vernengo, L; Mañana, G; Salamano, R; Carrasco, L; Lenne, M; Beaudry, P; Launay, J-M; Laplanche, J-L

    2005-04-26

    Inherited prion diseases are characterized by mutations in the PRNP gene encoding the prion protein (PrP). We report a novel missense mutation in the PRNP gene (resulting in a G114V mutation in PrP) in members of a Uruguayan family with clinical and histopathologic features of prion disease. Affected individuals were characterized by an early age at onset, initial neuropsychiatric symptoms, late dementia with prominent pyramidal and extrapyramidal symptoms, and long disease duration.

  7. The Expanding Universe of Prion Diseases

    OpenAIRE

    Watts, Joel C.; Aru Balachandran; David Westaway

    2006-01-01

    Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrP(C). Several mammalian species are affected by the diseases, and in the case of "mad cow disease" (BSE) the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases--including human d...

  8. [Current Trends in the Treatment of Prion Disease].

    Science.gov (United States)

    Tsuboi, Yoshio

    2015-07-01

    Prion disease refers to a group of neurodegenerative disorders characterized by a relentlessly progressing clinical course leading to death. The pathogenesis of prion disease is the conversion of a normal type prion protein (PrP(C)) into a pathological isoform with protease resistance (PrP(Sc)), which accumulates in the brain. A number of therapeutic agents, including quinacrine, doxycycline, and pentosan polysulphate have shown preventive effects against the conversion of PrP(C) into PrP(Sc) in experimental studies; however, none of these agents have shown satisfactory efficacy in clinical trials. As the clinical course of prion disease varies, the design of clinical trials has been particularly difficult. These limitations must be overcome, and it is necessary to determine a basis for clinical trials with the new candidate agents. PMID:26160821

  9. Lesion of the olfactory epithelium accelerates prion neuroinvasion and disease onset when prion replication is restricted to neurons.

    Directory of Open Access Journals (Sweden)

    Jenna Crowell

    Full Text Available Natural prion diseases of ruminants are moderately contagious and while the gastrointestinal tract is the primary site of prion agent entry, other mucosae may be entry sites in a subset of infections. In the current study we examined prion neuroinvasion and disease induction following disruption of the olfactory epithelium in the nasal mucosa since this site contains environmentally exposed olfactory sensory neurons that project directly into the central nervous system. Here we provide evidence for accelerated prion neuroinvasion and clinical onset from the olfactory mucosa after disruption and regeneration of the olfactory epithelium and when prion replication is restricted to neurons. In transgenic mice with neuron restricted replication of prions, there was a reduction in survival when the olfactory epithelium was disrupted prior to intranasal inoculation and there was >25% decrease in the prion incubation period. In a second model, the neurotropic DY strain of transmissible mink encephalopathy was not pathogenic in hamsters by the nasal route, but 50% of animals exhibited brain infection and/or disease when the olfactory epithelium was disrupted prior to intranasal inoculation. A time course analysis of prion deposition in the brain following loss of the olfactory epithelium in models of neuron-restricted prion replication suggests that neuroinvasion from the olfactory mucosa is via the olfactory nerve or brain stem associated cranial nerves. We propose that induction of neurogenesis after damage to the olfactory epithelium can lead to prion infection of immature olfactory sensory neurons and accelerate prion spread to the brain.

  10. Molecular Pathology of Human Prion Diseases

    Directory of Open Access Journals (Sweden)

    2009-03-01

    Full Text Available Prion diseases are fatal neurodegenerative conditions in humans and animals. In this review, we summarize the molecular background of phenotypic variability, relation of prion protein (PrP to other proteins associated with neurodegenerative diseases, and pathogenesis of neuronal vulnerability. PrP exists in different forms that may be present in both diseased and non-diseased brain, however, abundant disease-associated PrP together with tissue pathology characterizes prion diseases and associates with transmissibility. Prion diseases have different etiological background with distinct pathogenesis and phenotype. Mutations of the prion protein gene are associated with genetic forms. The codon 129 polymorphism in combination with the Western blot pattern of PrP after proteinase K digestion serves as a basis for molecular subtyping of sporadic Creutzfeldt-Jakob disease. Tissue damage may result from several parallel, interacting or subsequent pathways that involve cellular systems associated with synapses, protein processing, oxidative stress, autophagy, and apoptosis.

  11. Localization of A11-reactive oligomeric species in prion diseases

    DEFF Research Database (Denmark)

    Aidt, Frederik H; Hasholt, Lis F; Christiansen, Michael;

    2013-01-01

    To investigate in prion diseases the in-situ localization of prion protein oligomers sharing a common epitope with amyloid oligomers involved in a range of neurodegenerative diseases.......To investigate in prion diseases the in-situ localization of prion protein oligomers sharing a common epitope with amyloid oligomers involved in a range of neurodegenerative diseases....

  12. Prion protein self-interaction in prion disease therapy approaches

    NARCIS (Netherlands)

    Rigter, A.; Priem, J.; Langeveld, J.P.M.; Bossers, A.

    2011-01-01

    Transmissible spongiform encephalopathies (TSEs) or prion diseases are unique disorders that are not caused by infectious micro-organisms (bacteria or fungi), viruses or parasites, but rather seem to be the result of an infectious protein. TSEs are comprised of fatal neurodegenerative disorders affe

  13. Prion疾病%Prion disease

    Institute of Scientific and Technical Information of China (English)

    范学工

    1999-01-01

    @@ 人和动物的慢性中枢神经系统退行性疾病,如羊瘙痒症(scapie)、人克雅病(Creutzfeldt-Jakob Disease,CJD)和库鲁病(kuru)的病因一直不明,美国加州大学旧金山医学院的Prusiner教授经过近20年的研究,在1982年提出了Prion是CJD的病原因子假说,指出这是一种不同于细菌、病毒、真菌和寄生虫等病原微生物的新的致病蛋白质因子,并构建了prion-词[1].由Prion所引起的疾病称为Prion病(Prion Diseases).目前认为,Prion是所有传染性海绵状脑病(transmissible spongiform encephalopathies,TSE)的病原因子.

  14. Prion diseases of the brain; Prionenerkrankung des Gehirns

    Energy Technology Data Exchange (ETDEWEB)

    Lutz, Kira; Urbach, Horst [Universitaetsklinik Freiburg (Germany). Klinik fuer Neuroradiologie

    2015-09-15

    The prion diseases of the brain, especially Creutzfeldt-Jakob disease, are rare fatal neurodegenerative disorders. A definitive CJD diagnosis is currently only possible by a brain biopsy or post mortem autopsy. The diagnosis of Creutzfeldt-Jakob disease is based on clinical signs, pathognomonic EEG, on typical MRI findings and the examination of the cerebrospinal fluid. Using the MRI the diagnosis Creutzfeldt-Jakob disease can be confirmed or excluded with high certainty. The MRI examination should contain diffusion-weighted and FLAIR imaging sequences. This review article provides an overview of the prion diseases of the brain with the corresponding imaging findings.

  15. Atypical scrapie prions from sheep and lack of disease in transgenic mice overexpressing human prion protein.

    Science.gov (United States)

    Wadsworth, Jonathan D F; Joiner, Susan; Linehan, Jacqueline M; Balkema-Buschmann, Anne; Spiropoulos, John; Simmons, Marion M; Griffiths, Peter C; Groschup, Martin H; Hope, James; Brandner, Sebastian; Asante, Emmanuel A; Collinge, John

    2013-11-01

    Public and animal health controls to limit human exposure to animal prions are focused on bovine spongiform encephalopathy (BSE), but other prion strains in ruminants may also have zoonotic potential. One example is atypical/Nor98 scrapie, which evaded statutory diagnostic methods worldwide until the early 2000s. To investigate whether sheep infected with scrapie prions could be another source of infection, we inoculated transgenic mice that overexpressed human prion protein with brain tissue from sheep with natural field cases of classical and atypical scrapie, sheep with experimental BSE, and cattle with BSE. We found that these mice were susceptible to BSE prions, but disease did not develop after prolonged postinoculation periods when mice were inoculated with classical or atypical scrapie prions. These data are consistent with the conclusion that prion disease is less likely to develop in humans after exposure to naturally occurring prions of sheep than after exposure to epizootic BSE prions of ruminants.

  16. The structure of prion: is it enough for interpreting the diverse phenotypes of prion diseases?

    Institute of Scientific and Technical Information of China (English)

    Chan Tian; Xiaoping Dong

    2013-01-01

    Prion diseases,or transmissible spongiform encephalopathies,are neurodegenerative diseases,which affect human and many species of animals with 100% fatality rate.The most accepted etiology for prion disease is 'prion',which arises from the conversion from cellular PrPC to the pathological PrPsc.This review discussed the characteristic structure of PrP,including PRNP gene,PrPC,PrPSc,PrP amyloid,and prion strains.

  17. On the statistical mechanics of prion diseases

    OpenAIRE

    Slepoy, A.; Singh, R. R. P.; Pázmándi, F.; Kulkarni, R.N.; Cox, D L

    2001-01-01

    We simulate a two-dimensional, lattice based, protein-level statistical mechanical model for prion diseases (e.g., Mad Cow disease) with concommitant prion protein misfolding and aggregation. Our simulations lead us to the hypothesis that the observed broad incubation time distribution in epidemiological data reflect fluctuation dominated growth seeded by a few nanometer scale aggregates, while much narrower incubation time distributions for innoculated lab animals arise from statistical self...

  18. Prion disease. The characteristics and diagnostic points in Japan

    International Nuclear Information System (INIS)

    Prion disease develops when normal prion proteins change into transmissible abnormal prion proteins and the converted proteins accumulate in the brain. The Japanese Creutzfeldt-Jakob Disease (CJD) Surveillance Committee has identified 1,320 patients with prion diseases in the 10 years since 1999 (classified into 3 types: sporadic, 77.2%; hereditary, 16.7%; and environmentally acquired, 6.1%). Compared with patients in other countries, a relatively larger number of Japanese patients characteristically have dura mater graft-associated CJD and hereditary prion diseases. All the environmentally acquired cases, except 1 case of variant CJD, were acquired from dura grafts. Although most patients were diagnosed with a classical subtype of sporadic CJD (sCJD), whose features include rapidly progressing dementia, myoclonus, hyperintensity in the cerebral cortex and basal ganglia in diffusion-weighted magnetic resonance imaging, and periodic synchronous discharge in electroencephalography, the number of cases with atypical symptoms, such as MM2 (0.8%), MV2 (0.2%), VV1 (0%), and VV2 (0.2%) subtypes of sCJD cases, was not negligible. Appropriate diagnosis should be made based on clinical features, neuroradiological findings, cerebrospinal fluid (CSF) findings (14-3-3 and total tau proteins), and genetic analysis of polymorphisms. Hereditary prion diseases are classified into 3 major phenotypes: familial CJD (fCJD); Gerstmann-Straeussler-Scheinker disease (GSS), which mainly presents as spinocerebellar ataxia; and fatal familial insomnia. Many mutations of the prion protein gene have been identified, but V1801 (fCJD), P102L (GSS), and E200K (fCJD) mutations were the most common among the fCJD cases in Japan. Without a family history, genetic testing is necessary to distinguish even seemingly ''sporadic'' CJD from fCJD. Accurate diagnosis is important for clarification of the pathological process, prevention of secondary infection, and also psychological support. (author)

  19. Genesis of mammalian prions: from non-infectious amyloid fibrils to a transmissible prion disease.

    Directory of Open Access Journals (Sweden)

    Natallia Makarava

    2011-12-01

    Full Text Available The transmissible agent of prion disease consists of a prion protein in its abnormal, β-sheet rich state (PrP(Sc, which is capable of replicating itself according to the template-assisted mechanism. This mechanism postulates that the folding pattern of a newly recruited polypeptide chain accurately reproduces that of a PrP(Sc template. Here we report that authentic PrP(Sc and transmissible prion disease can be generated de novo in wild type animals by recombinant PrP (rPrP amyloid fibrils, which are structurally different from PrP(Sc and lack any detectable PrP(Sc particles. When induced by rPrP fibrils, a long silent stage that involved two serial passages preceded development of the clinical disease. Once emerged, the prion disease was characterized by unique clinical, neuropathological, and biochemical features. The long silent stage to the disease was accompanied by significant transformation in neuropathological properties and biochemical features of the proteinase K-resistant PrP material (PrPres before authentic PrP(Sc evolved. The current work illustrates that transmissible prion diseases can be induced by PrP structures different from that of authentic PrP(Sc and suggests that a new mechanism different from the classical templating exists. This new mechanism designated as "deformed templating" postulates that a change in the PrP folding pattern from the one present in rPrP fibrils to an alternative specific for PrP(Sc can occur. The current work provides important new insight into the mechanisms underlying genesis of the transmissible protein states and has numerous implications for understanding the etiology of neurodegenerative diseases.

  20. Epidemiological characteristics of human prion diseases.

    Science.gov (United States)

    Chen, Cao; Dong, Xiao-Ping

    2016-01-01

    Human prion diseases are a group of transmissible, progressive, and invariably fatal neurodegenerative disorders, which include Kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia. Human prion diseases affect approximately 1-2 persons per million worldwide annually, occurring in sporadic, inherited, and acquired forms. These diseases have attracted both scientific and public attention not only because of their mysterious pathogen, but also due to their considerable threat to public health since the emergence of the variant CJD.There are still no specific therapeutic and prophylactic interventions available for prion diseases, thus active surveillance of human prion diseases is critical for disease control and prevention. Since 1993, CJD surveillance systems have been established in many countries and regions, and several long-term multinational cooperative projects have been conducted.In this paper, the epidemiological characteristics of various human prion diseases and the active surveillance systems pertaining to them in different countries and regions are summarized and reviewed. PMID:27251305

  1. The expanding universe of prion diseases.

    Directory of Open Access Journals (Sweden)

    Joel C Watts

    2006-03-01

    Full Text Available Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrP(C. Several mammalian species are affected by the diseases, and in the case of "mad cow disease" (BSE the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases--including human diseases variant Creutzfeldt-Jakob disease (vCJD and sporadic fatal insomnia (sFI, bovine amyloidotic spongiform encephalopathy (BASE, and Nor98 of sheep--have been identified in the last ten years, and chronic wasting disease (CWD of North American deer (Odocoileus Specis and Rocky Mountain elk (Cervus elaphus nelsoni is undergoing a dramatic spread across North America. While amplification (BSE and dissemination (CWD, commercial sourcing of cervids from the wild and movement of farmed elk can be attributed to human activity, the origins of emergent prion diseases cannot always be laid at the door of humankind. Instead, the continued appearance of new outbreaks in the form of "sporadic" disease may be an inevitable outcome in a situation where the replicating pathogen is host-encoded.

  2. The expanding universe of prion diseases.

    Directory of Open Access Journals (Sweden)

    2006-03-01

    Full Text Available Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrP(C. Several mammalian species are affected by the diseases, and in the case of "mad cow disease" (BSE the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases-including human diseases variant Creutzfeldt-Jakob disease (vCJD and sporadic fatal insomnia (sFI, bovine amyloidotic spongiform encephalopathy (BASE, and Nor98 of sheep-have been identified in the last ten years, and chronic wasting disease (CWD of North American deer (Odocoileus Specis and Rocky Mountain elk (Cervus elaphus nelsoni is undergoing a dramatic spread across North America. While amplification (BSE and dissemination (CWD, commercial sourcing of cervids from the wild and movement of farmed elk can be attributed to human activity, the origins of emergent prion diseases cannot always be laid at the door of humankind. Instead, the continued appearance of new outbreaks in the form of "sporadic" disease may be an inevitable outcome in a situation where the replicating pathogen is host-encoded.

  3. Prion Disease: Learn the Facts. Avoid Exposure.

    Centers for Disease Control (CDC) Podcasts

    2011-05-23

    This podcast discusses prion diseases and the risk of exposure associated with some common activities.  Created: 5/23/2011 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 5/23/2011.

  4. M cell-depletion blocks oral prion disease pathogenesis

    OpenAIRE

    Donaldson, D S; Kobayashi, A; Ohno, H.; Yagita, H; Williams, I R; Mabbott, N A

    2012-01-01

    Many prion diseases are orally acquired. Our data show that after oral exposure, early prion replication upon follicular dendritic cells (FDC) in Peyer's patches is obligatory for the efficient spread of disease to the brain (termed neuroinvasion). For prions to replicate on FDC within Peyer's patches after ingestion of a contaminated meal, they must first cross the gut epithelium. However, the mechanism through which prions are conveyed into Peyer's patches is uncertain. Within the follicle-...

  5. Transmissible Spongiform Encephalopathies (Prion Diseases)

    Science.gov (United States)

    ... called bovine spongiform encephalopathy (BSE), also known as "mad cow disease." Other TSEs found in animals include scrapie, which ... and Worldwide NINDS Clinical Trials Organizations Column1 Column2 Creutzfeldt-Jakob Disease (CJD) Foundation Inc. 341 W. 38th Street, Suite ...

  6. Prion diseases and the gastrointestinal tract.

    Science.gov (United States)

    Davies, G A; Bryant, Adam R; Reynolds, John D; Jirik, Frank R; Sharkey, Keith A

    2006-01-01

    The gastrointestinal (GI) tract plays a central role in the pathogenesis of transmissible spongiform encephalopathies. These are human and animal diseases that include bovine spongiform encephalopathy, scrapie and Creutzfeldt-Jakob disease. They are uniformly fatal neurological diseases, which are characterized by ataxia and vacuolation in the central nervous system. Although they are known to be caused by the conversion of normal cellular prion protein to its infectious conformational isoform (PrPsc) the process by which this isoform is propagated and transported to the brain remains poorly understood. M cells, dendritic cells and possibly enteroendocrine cells are important in the movement of infectious prions across the GI epithelium. From there, PrPsc propagation requires B lymphocytes, dendritic cells and follicular dendritic cells of Peyer's patches. The early accumulation of the disease-causing agent in the plexuses of the enteric nervous system supports the contention that the autonomic nervous system is important in disease transmission. This is further supported by the presence of PrPsc in the ganglia of the parasympathetic and sympathetic nerves that innervate the GI tract. Additionally, the lymphoreticular system has been implicated as the route of transmission from the gut to the brain. Although normal cellular prion protein is found in the enteric nervous system, its role has not been characterized. Further research is required to understand how the cellular components of the gut wall interact to propagate and transmit infectious prions to develop potential therapies that may prevent the progression of transmissible spongiform encephalopathies. PMID:16432555

  7. [Prion diseases: what is the role of dendritic cells in the pathogenesis of transmissible prion diseases?].

    Science.gov (United States)

    Bachy, Véronique; Aucouturier, Pierre

    2010-01-01

    Prion diseases are caused by the transconformation of a normal cellular protein, PrPc, into an infectious isoform, PrPsc, which ultimately triggers neuronal death. They are always fatal and, after transmission, they feature long incubation periods, during which prions accumulate in lymphoid tissues, infect nerves and progress to the central nervous system. In lymphoid organs, prions replicate and accumulate in follicular dendritic cells. Suppressing these cells slows down the neuro-invasion but does not totally abrogate it. This review examines the current knowledge in the roles of hematopoietic dendritic cells at different steps of the pathogenesis of prion diseases. Dendritic cells endocytose inoculated prions, permit their crossing of the intestinal epithelium and then migrate and transport them to lymphoid organs. They can carry prions to sites of neuroinvasion, and establish contacts with axons in peripheral lymph nodes or even after passage of the blood-brain barrier. However, results in the literature on the role of dendritic cells differ according to the host or the prion strain. PMID:20619164

  8. Prion disease tempo determined by host-dependent substrate reduction

    NARCIS (Netherlands)

    Mays, C.E.; Kim, C.; Haldiman, T.; Merwe, v.d. J.; Lau, A.; Yang, J.; Grams, J.; Bari, Di M.A.; Nonno, R.; Telling, G.C.; Kong, Q.; Langeveld, J.P.M.; McKenzie, D.; Westaway, D.; Safar, J.G.

    2014-01-01

    The symptoms of prion infection can take years or decades to manifest following the initial exposure. Molecular markers of prion disease include accumulation of the misfolded prion protein (PrPSc), which is derived from its cellular precursor (PrPC), as well as downregulation of the PrP-like Shadoo

  9. Prion Diseases and the Gastrointestinal Tract

    OpenAIRE

    Davies, Gwynivere A; Bryant, Adam R; John D. Reynolds; Jirik, Frank R.; Keith A Sharkey

    2006-01-01

    The gastrointestinal (GI) tract plays a central role in the pathogenesis of transmissible spongiform encephalopathies. These are human and animal diseases that include bovine spongiform encephalopathy, scrapie and Creutzfeldt-Jakob disease. They are uniformly fatal neurological diseases, which are characterized by ataxia and vacuolation in the central nervous system. Alhough they are known to be caused by the conversion of normal cellular prion protein to its infectious conformational isoform...

  10. Involvement of Endogenous Retroviruses in Prion Diseases

    Directory of Open Access Journals (Sweden)

    Yong-Sun Kim

    2013-08-01

    Full Text Available For millions of years, vertebrates have been continuously exposed to infection by retroviruses. Ancient retroviral infection of germline cells resulted in the formation and accumulation of inherited retrovirus sequences in host genomes. These inherited retroviruses are referred to as endogenous retroviruses (ERVs, and recent estimates have revealed that a significant portion of animal genomes is made up of ERVs. Although various host factors have suppressed ERV activation, both positive and negative functions have been reported for some ERVs in normal and abnormal physiological conditions, such as in disease states. Similar to other complex diseases, ERV activation has been observed in prion diseases, and this review will discuss the potential involvement of ERVs in prion diseases.

  11. Prion Disease Induces Alzheimer Disease-Like Neuropathologic Changes

    Science.gov (United States)

    Tousseyn, Thomas; Bajsarowicz, Krystyna; Sánchez, Henry; Gheyara, Ania; Oehler, Abby; Geschwind, Michael; DeArmond, Bernadette; DeArmond, Stephen J.

    2016-01-01

    We examined the brains of 266 patients with prion diseases (PrionD) and found that 46 (17%) had Alzheimer disease (AD)-like changes. To explore potential mechanistic links between PrionD and AD, we exposed human brain aggregates (Hu BrnAggs) to brain homogenate from a patient with sporadic Creutzfeldt-Jakob disease (CJD) and found that the neurons in the Hu BrnAggs produced many β-amyloid (β42) inclusions, whereas uninfected, control-exposed Hu BrnAggs did not. Western blots of 20-pooled CJD-infected BrnAggs verified higher Aβ42 levels than controls. We next examined the CA1 region of the hippocampus from 14 patients with PrionD and found that 5 patients had low levels of scrapie-associated prion protein (PrPSc), many Aβ42 intraneuronal inclusions, low APOE-4, and no significant nerve cell loss. Seven patients had high levels of PrPSc, low Aβ42, high APOE-4 and 40% nerve cell loss, suggesting that APOE-4 and PrPSc together cause neuron loss in PrionD. There were also increased levels of hyperphosphorylated tau protein (Hτ) and Hτ-positive neuropil threads and neuron bodies in both PrionD and AD groups. The brains of 6 age-matched control patients without dementia did not contain Aβ42 deposits; however, there were rare Hτ-positive threads in 5 controls and 2 controls had a few Hτ-positive nerve cell bodies. We conclude that PrionD may trigger biochemical changes similar to AD and suggest that PrionD are diseases of PrPSc, Aβ42, APOE-4 and abnormal tau. PMID:26226132

  12. Fatal transmissible amyloid encephalopathy: a new type of prion disease associated with lack of prion protein membrane anchoring.

    Directory of Open Access Journals (Sweden)

    Bruce Chesebro

    2010-03-01

    Full Text Available Prion diseases are fatal neurodegenerative diseases of humans and animals characterized by gray matter spongiosis and accumulation of aggregated, misfolded, protease-resistant prion protein (PrPres. PrPres can be deposited in brain in an amyloid-form and/or non-amyloid form, and is derived from host-encoded protease-sensitive PrP (PrPsen, a protein normally anchored to the plasma membrane by glycosylphosphatidylinositol (GPI. Previously, using heterozygous transgenic mice expressing only anchorless PrP, we found that PrP anchoring to the cell membrane was required for typical clinical scrapie. However, in the present experiments, using homozygous transgenic mice expressing two-fold more anchorless PrP, scrapie infection induced a new fatal disease with unique clinical signs and altered neuropathology, compared to non-transgenic mice expressing only anchored PrP. Brain tissue of transgenic mice had high amounts of infectivity, and histopathology showed dense amyloid PrPres plaque deposits without gray matter spongiosis. In contrast, infected non-transgenic mice had diffuse non-amyloid PrPres deposits with significant gray matter spongiosis. Brain graft studies suggested that anchored PrPsen expression was required for gray matter spongiosis during prion infection. Furthermore, electron and light microscopic studies in infected transgenic mice demonstrated several pathogenic processes not seen in typical prion disease, including cerebral amyloid angiopathy and ultrastructural alterations in perivascular neuropil. These findings were similar to certain human familial prion diseases as well as to non-prion human neurodegenerative diseases, such as Alzheimer's disease.

  13. MAD COW DISEASE: New Recruits for French Prion Research.

    Science.gov (United States)

    Casassus, B

    2000-12-01

    As panic over "mad cow disease" engulfs France and threatens to spread to other countries in Western Europe, French research minister Roger-Gérard Schwartzenberg last week unveiled detailed plans for spending $27 million the government has earmarked for prion disease research in 2001. Next year's budget for studying prions--infectious, abnormal proteins linked to bovine spongiform encephalopathy and its human form, variant Creutzfeldt-Jakob disease--will triple France's current prion research spending. PMID:17798203

  14. Myiasis as a risk factor for prion diseases in humans.

    Science.gov (United States)

    Lupi, O

    2006-10-01

    Prion diseases are transmissible spongiform encephalopathies of humans and animals. The oral route is clearly associated with some prion diseases, according to the dissemination of bovine spongiform encephalopathy (BSE or mad cow disease) in cattle and kuru in humans. However, other prion diseases such as scrapie (in sheep) and chronic wasting disease (CWD) (in cervids) cannot be explained in this way and are probably more associated with a pattern of horizontal transmission in both domestic and wild animals. The skin and mucous membranes are a potential target for prion infections because keratinocytes and lymphocytes are susceptible to the abnormal infective isoform of the prion protein. Iatrogenic transmission of Creutzfeldt-Jakob disease (CJD) was also recognized after corneal transplants in humans and scrapie was successfully transmitted to mice after ocular instillation of infected brain tissue, confirming that these new routes could also be important in prion infections. Some ectoparasites have been proven to harbour prion rods in laboratory experiments. Prion rods were identified in both fly larvae and pupae; adult flies are also able to express prion proteins. The most common causes of myiasis in cattle and sheep, closely related animals with previous prion infections, are Hypoderma bovis and Oestrus ovis, respectively. Both species of flies present a life cycle very different from human myiasis, as they have a long contact with neurological structures, such as spinal canal and epidural fat, which are potentially rich in prion rods. Ophthalmomyiases in humans is commonly caused by both species of fly larvae worldwide, providing almost direct contact with the central nervous system (CNS). The high expression of the prion protein on the skin and mucosa and the severity of the inflammatory response to the larvae could readily increase the efficiency of transmission of prions in both animals and humans. PMID:16987255

  15. Prionet Canada: a network of centres of excellence for research into prions and prion diseases.

    Science.gov (United States)

    Wong, Michelle; Toth, Janie; Haney, Sandra; Tyshenko, Michael G; Darshan, Shalu; Krewski, Daniel; Leighton, Frederick A; Westaway, David; Moore, Stephen S; Ricketts, Maura; Cashman, Neil

    2009-01-01

    PrioNet Canada's strength in basic, applied, and social research is helping to solve the food, health safety, and socioeconomic problems associated with prion diseases. Prion diseases are transmissible, fatal neurodegenerative diseases of humans and animals. Examples of prion diseases include bovine spongiform encephalopathy (BSE, commonly known as "mad cow" disease), Creutzfeldt-Jakob disease in humans, and chronic wasting disease (CWD) in deer and elk. As of March 31, 2008, PrioNet's interdisciplinary network included 62 scientific members, 5 international collaborators, and more than 150 students and young professionals working in partnership with 25 different government, nongovernment, and industry partners. PrioNet's activities are developing strategies based on a sustained, rational approach that will mitigate, and ultimately control, prion diseases in Canada. PMID:19697232

  16. M cell-depletion blocks oral prion disease pathogenesis.

    Science.gov (United States)

    Donaldson, D S; Kobayashi, A; Ohno, H; Yagita, H; Williams, I R; Mabbott, N A

    2012-03-01

    Many prion diseases are orally acquired. Our data show that after oral exposure, early prion replication upon follicular dendritic cells (FDC) in Peyer's patches is obligatory for the efficient spread of disease to the brain (termed neuroinvasion). For prions to replicate on FDC within Peyer's patches after ingestion of a contaminated meal, they must first cross the gut epithelium. However, the mechanism through which prions are conveyed into Peyer's patches is uncertain. Within the follicle-associated epithelium overlying Peyer's patches are microfold cells (M cells), unique epithelial cells specialized for the transcytosis of particles. We show that following M cell-depletion, early prion accumulation upon FDC in Peyer's patches is blocked. Furthermore, in the absence of M cells at the time of oral exposure, neuroinvasion and disease development are likewise blocked. These data suggest M cells are important sites of prion uptake from the gut lumen into Peyer's patches. PMID:22294048

  17. A naturally occurring variant of the human prion protein completely prevents prion disease.

    Science.gov (United States)

    Asante, Emmanuel A; Smidak, Michelle; Grimshaw, Andrew; Houghton, Richard; Tomlinson, Andrew; Jeelani, Asif; Jakubcova, Tatiana; Hamdan, Shyma; Richard-Londt, Angela; Linehan, Jacqueline M; Brandner, Sebastian; Alpers, Michael; Whitfield, Jerome; Mead, Simon; Wadsworth, Jonathan D F; Collinge, John

    2015-06-25

    Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G→V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.

  18. Implications of prion diseases for dentistry: an update.

    Science.gov (United States)

    Palacios-Sánchez, Begoña; Esparza-Gómez, Germán C; Campo-Trapero, Julián; Cerero-Lapiedra, Rocío

    2008-03-01

    Prions are normal proteins present in all mammals, especially in the central nervous system (CNS) and lymphoreticular tissue. Their transformation into a highly infectious molecule gives rise to a group of diseases known as transmissible spongiform encephalopathies (TSEs), which cause vacuolar degeneration of gray matter and produce a fatal neurodegenerative disorder. Prion diseases have attracted considerable attention in recent years, and this review of the literature was designed to determine their implications for dentistry, studying the possibility of cross-transmission in the dental office and describing their oral manifestations. The main oral manifestations are dysphagia, dysarthria, paresthesias, dysesthesias, and dysgeusia. The most frequently involved oral tissues are the trigeminal ganglion, posterior third of the tongue, tonsils, and, much less commonly, alveolar nerves, gingiva, and salivary glands. Although no contagion has been reported in the dental setting to date, prions resist the usual dental sterilization systems and transmission of this type of disease remains a potential risk. It is therefore important for dentists to be aware of these diseases, to identify high-risk patients by obtaining an adequate clinical history, and to know the appropriate procedures to be followed. PMID:18280965

  19. Effective Gene Therapy in a Mouse Model of Prion Diseases

    OpenAIRE

    Karine Toupet; Valérie Compan; Carole Crozet; Chantal Mourton-Gilles; Nadine Mestre-Francés; Françoise Ibos; Pierre Corbeau; Jean-Michel Verdier; Véronique Perrier

    2008-01-01

    Classical drug therapies against prion diseases have encountered serious difficulties. It has become urgent to develop radically different therapeutic strategies. Previously, we showed that VSV-G pseudotyped FIV derived vectors carrying dominant negative mutants of the PrP gene are efficient to inhibit prion replication in chronically prion-infected cells. Besides, they can transduce neurons and cells of the lymphoreticular system, highlighting their potential use in gene therapy approaches. ...

  20. Human prion diseases in the United States.

    Directory of Open Access Journals (Sweden)

    Robert C Holman

    Full Text Available BACKGROUND: Prion diseases are a family of rare, progressive, neurodegenerative disorders that affect humans and animals. The most common form of human prion disease, Creutzfeldt-Jakob disease (CJD, occurs worldwide. Variant CJD (vCJD, a recently emerged human prion disease, is a zoonotic foodborne disorder that occurs almost exclusively in countries with outbreaks of bovine spongiform encephalopathy. This study describes the occurrence and epidemiology of CJD and vCJD in the United States. METHODOLOGY/PRINCIPAL FINDINGS: Analysis of CJD and vCJD deaths using death certificates of US residents for 1979-2006, and those identified through other surveillance mechanisms during 1996-2008. Since CJD is invariably fatal and illness duration is usually less than one year, the CJD incidence is estimated as the death rate. During 1979 through 2006, an estimated 6,917 deaths with CJD as a cause of death were reported in the United States, an annual average of approximately 247 deaths (range 172-304 deaths. The average annual age-adjusted incidence for CJD was 0.97 per 1,000,000 persons. Most (61.8% of the CJD deaths occurred among persons >or=65 years of age for an average annual incidence of 4.8 per 1,000,000 persons in this population. Most deaths were among whites (94.6%; the age-adjusted incidence for whites was 2.7 times higher than that for blacks (1.04 and 0.40, respectively. Three patients who died since 2004 were reported with vCJD; epidemiologic evidence indicated that their infection was acquired outside of the United States. CONCLUSION/SIGNIFICANCE: Surveillance continues to show an annual CJD incidence rate of about 1 case per 1,000,000 persons and marked differences in CJD rates by age and race in the United States. Ongoing surveillance remains important for monitoring the stability of the CJD incidence rates, and detecting occurrences of vCJD and possibly other novel prion diseases in the United States.

  1. Primary transmission of chronic wasting disease versus scrapie prions from small ruminants to transgenic mice expressing ovine or cervid prion protein.

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    Madsen-Bouterse, Sally A; Schneider, David A; Zhuang, Dongyue; Dassanayake, Rohana P; Balachandran, Aru; Mitchell, Gordon B; O'Rourke, Katherine I

    2016-09-01

    Development of mice expressing either ovine (Tg338) or cervid (TgElk) prion protein (PrP) have aided in characterization of scrapie and chronic wasting disease (CWD), respectively. Experimental inoculation of sheep with CWD prions has demonstrated the potential for interspecies transmission but, infection with CWD versus classical scrapie prions may be difficult to differentiate using validated diagnostic platforms. In this study, mouse bioassay in Tg338 and TgElk was utilized to evaluate transmission of CWD versus scrapie prions from small ruminants. Mice (≥5 per homogenate) were inoculated with brain homogenates from clinically affected sheep or goats with naturally acquired classical scrapie, white-tailed deer with naturally acquired CWD (WTD-CWD) or sheep with experimentally acquired CWD derived from elk (sheep-passaged-CWD). Survival time (time to clinical disease) and attack rates (brain accumulation of protease resistant PrP, PrPres) were determined. Inoculation with classical scrapie prions resulted in clinical disease and 100 % attack rates in Tg338, but no clinical disease at endpoint (>300 days post-inoculation, p.i.) and low attack rates (6.8 %) in TgElk. Inoculation with WTD-CWD prions yielded no clinical disease or brain PrPres accumulation in Tg338 at endpoint (>500 days p.i.), but rapid onset of clinical disease (~121 days p.i.) and 100 % attack rate in TgElk. Sheep-passaged-CWD resulted in transmission to both mouse lines with 100 % attack rates at endpoint in Tg338 and an attack rate of ~73 % in TgElk with some culled due to clinical disease. These primary transmission observations demonstrate the potential of bioassay in Tg338 and TgElk to help differentiate possible infection with CWD versus classical scrapie prions in sheep and goats.

  2. Quantitative EEG parameters correlate with the progression of human prion diseases

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    Wehner, Tim; Lowe, Jessica; Porter, Marie-Claire; Kenny, Joanna; Thompson, Andrew; Rudge, Peter; Collinge, John; Mead, Simon

    2016-01-01

    Background Prion diseases are universally fatal and often rapidly progressive neurodegenerative diseases. EEG has long been used in the diagnosis of sporadic Creutzfeldt-Jakob disease; however, the characteristic waveforms do not occur in all types of prion diseases. Here, we re-evaluate the utility of EEG by focusing on the development of biomarkers. We test whether abnormal quantitative EEG parameters can be used to measure disease progression in prion diseases or predict disease onset in healthy individuals at risk of disease. Methods In the National Prion Monitoring Cohort study, we did quantitative encephalography on 301 occasions in 29 healthy controls and 67 patients with prion disease. The patients had either inherited prion disease or sporadic Creutzfeldt-Jakob disease. We computed the main background frequency, the α and θ power and the α/θ power ratio, then averaged these within 5 electrode groups. These measurements were then compared among participant groups and correlated with functional and cognitive scores cross-sectionally and longitudinally. Results We found lower main background frequency, α power and α/θ power ratio and higher θ power in patients compared to control participants. The main background frequency, the power in the α band and the α/θ power ratio also differed in a consistent way among the patient groups. Moreover, the main background frequency and the α/θ power ratio correlated significantly with functional and cognitive scores. Longitudinally, change in these parameters also showed significant correlation with the change in clinical and cognitive scores. Conclusions Our findings support the use of quantitative EEG to follow the progression of prion disease, with potential to help evaluate the treatment effects in future clinical-trials. PMID:27413165

  3. Ultraviolet-ozone treatment reduces levels of disease-associated prion protein and prion infectivity

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    Johnson, C.J.; Gilbert, P.; McKenzie, D.; Pedersen, J.A.; Aiken, Judd M.

    2009-01-01

    Background. Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative diseases caused by novel infectious agents referred to as prions. Prions appear to be composed primarily, if not exclusively, of a misfolded isoform of the cellular prion protein. TSE infectivity is remarkably stable and can resist many aggressive decontamination procedures, increasing human, livestock and wildlife exposure to TSEs. Findings. We tested the hypothesis that UV-ozone treatment reduces levels of the pathogenic prion protein and inactivates the infectious agent. We found that UV-ozone treatment decreased the carbon and prion protein content in infected brain homogenate to levels undetectable by dry-ashing carbon analysis or immunoblotting, respectively. After 8 weeks of ashing, UV-ozone treatment reduced the infectious titer of treated material by a factor of at least 105. A small amount of infectivity, however, persisted despite UV-ozone treatment. When bound to either montmorillonite clay or quartz surfaces, PrPTSE was still susceptible to degradation by UV-ozone. Conclusion. Our findings strongly suggest that UV-ozone treatment can degrade pathogenic prion protein and inactivate prions, even when the agent is associated with surfaces. Using larger UV-ozone doses or combining UV-ozone treatment with other decontaminant methods may allow the sterilization of TSE-contaminated materials. ?? 2009 Aiken et al; licensee BioMed Central Ltd.

  4. The Medical Research Council prion disease rating scale: a new outcome measure for prion disease therapeutic trials developed and validated using systematic observational studies.

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    Thompson, Andrew G B; Lowe, Jessica; Fox, Zoe; Lukic, Ana; Porter, Marie-Claire; Ford, Liz; Gorham, Michele; Gopalakrishnan, Gosala S; Rudge, Peter; Walker, A Sarah; Collinge, John; Mead, Simon

    2013-04-01

    Progress in therapeutics for rare disorders like prion disease is impeded by the lack of validated outcome measures and a paucity of natural history data derived from prospective observational studies. The first analysis of the U.K. National Prion Monitoring Cohort involved 1337 scheduled clinical assessments and 479 telephone assessments in 437 participants over 373 patient-years of follow-up. Scale development has included semi-quantitative and qualitative carer interviews, item response modelling (Rasch analysis), inter-rater reliability testing, construct analysis and correlation with several existing scales. The proposed 20-point Medical Research Council prion disease rating scale assesses domains of cognitive function, speech, mobility, personal care/feeding and continence, according to their relative importance documented by carer interviews. It is quick and simple to administer, and has been validated for use by doctors and nurses and for use over the telephone, allowing for frequent assessments that capture the rapid change typical of these diseases. The Medical Research Council Scale correlates highly with widely used cognitive and single item scales, but has substantial advantages over these including minimal floor effects. Three clear patterns of decline were observed using the scale: fast linear decline, slow linear decline (usually inherited prion disease) and in some patients, decline followed by a prolonged preterminal plateau at very low functional levels. Rates of decline and progress through milestones measured using the scale vary between sporadic, acquired and inherited prion diseases following clinical expectations. We have developed and validated a new functionally-oriented outcome measure and propose that future clinical trials in prion disease should collect data compatible with this scale, to allow for combined and comparative analyses. Such approaches may be advantageous in orphan conditions, where single studies of feasible duration will

  5. Rapidly progressive dementias and the treatment of human prion diseases

    Science.gov (United States)

    Lyketsos, Constantine G

    2012-01-01

    Importance of the field Rapidly progressive dementia (RPD) has many possible etiologies and definitive treatment is reliant upon an accurate diagnosis from an appropriate diagnostic work-up. A large portion of the neurodegenerative causes of RPD are due to prion diseases (e.g., Creutzfeldt–Jakob disease). The study of prion diseases, for which there is no currently available treatment, has public health implications and is becoming increasingly more relevant to our understanding of other protein misfolding disorders including Alzheimer’s disease, frontotemporal degeneration, and Parkinson’s disease. Areas covered in this review This article begins with an overview of the etiologies and diagnostic work-up of RPD followed by a detailed review of the literature concerning the treatment of human prion diseases (1971 to present). What the reader will gain The reader will understand the differential diagnosis and work-up of RPD as it pertains to its treatment, as well as an in-depth understanding of treatments of human prion diseases. Take home message An accurate diagnosis of the cause of RPD is of paramount importance when determining appropriate treatment. Most studies of the treatment for human prion diseases are case reports or case series, and results from only one randomized, placebo-controlled study have been reported in the literature (flupirtine). Studies have been hindered by disease heterogeneity and lack of standardized outcome measures. Although no effective prion disease treatment has been revealed through these studies, they provide important considerations for future studies. PMID:21091283

  6. Prion diseases and adult neurogenesis: how do prions counteract the brain's endogenous repair machinery?

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    Relaño-Ginés, Aroa; Lehmann, Sylvain; Crozet, Carole

    2014-01-01

    Scientific advances in stem cell biology and adult neurogenesis have raised the hope that neurodegenerative disorders could benefit from stem cell-based therapy. Adult neurogenesis might be part of the physiological regenerative process, however it might become impaired by the disease's mechanism and therefore contribute to neurodegeneration. In prion disorders this endogenous repair system has rarely been studied. Whether adult neurogenesis plays a role or not in brain repair or in the propagation of prion pathology remains unclear. We have recently investigated the status of adult neural stem cells isolated from prion-infected mice. We were able to show that neural stem cells accumulate and replicate prions thus resulting in an alteration of their neuronal destiny. We also reproduced these results in adult neural stem cells, which were infected in vitro. The fact that endogenous adult neurogenesis could be altered by the accumulation of misfolded prion protein represents another great challenge. Inhibiting prion propagation in these cells would thus help the endogenous neurogenesis to compensate for the injured neuronal system. Moreover, understanding the endogenous modulation of the neurogenesis system would help develop effective neural stem cell-based therapies.

  7. Transmission of chronic wasting disease identifies a prion strain causing cachexia and heart infection in hamsters.

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    Richard A Bessen

    Full Text Available Chronic wasting disease (CWD is an emerging prion disease of free-ranging and captive cervids in North America. In this study we established a rodent model for CWD in Syrian golden hamsters that resemble key features of the disease in cervids including cachexia and infection of cardiac muscle. Following one to three serial passages of CWD from white-tailed deer into transgenic mice expressing the hamster prion protein gene, CWD was subsequently passaged into Syrian golden hamsters. In one passage line there were preclinical changes in locomotor activity and a loss of body mass prior to onset of subtle neurological symptoms around 340 days. The clinical symptoms included a prominent wasting disease, similar to cachexia, with a prolonged duration. Other features of CWD in hamsters that were similar to cervid CWD included the brain distribution of the disease-specific isoform of the prion protein, PrP(Sc, prion infection of the central and peripheral neuroendocrine system, and PrP(Sc deposition in cardiac muscle. There was also prominent PrP(Sc deposition in the nasal mucosa on the edge of the olfactory sensory epithelium with the lumen of the nasal airway that could have implications for CWD shedding into nasal secretions and disease transmission. Since the mechanism of wasting disease in prion diseases is unknown this hamster CWD model could provide a means to investigate the physiological basis of cachexia, which we propose is due to a prion-induced endocrinopathy. This prion disease phenotype has not been described in hamsters and we designate it as the 'wasting' or WST strain of hamster CWD.

  8. Alteration of the chronic wasting disease species barrier by in vitro prion amplification

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    Kurt, Timothy D.; Seelig, Davis M.; Schneider, Jay R.; Johnson, Christopher J.; Telling, Glenn C.; Heisey, Dennis M.; Hoover, Edward A.

    2011-01-01

    Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of cervids now detected in 19 states of the United States, three Canadian provinces, and South Korea. Whether noncervid species can be infected by CWD and thereby serve as reservoirs for the infection is not known. To investigate this issue, we previously used serial protein misfolding cyclic amplification (sPMCA) to demonstrate that CWD prions can amplify in brain homogenates from several species sympatric with cervids, including prairie voles (Microtus ochrogaster) and field mice (Peromyscus spp.). Here, we show that prairie voles are susceptible to mule deer CWD prions in vivo and that sPMCA amplification of CWD prions in vole brain enhances the infectivity of CWD for this species. Prairie voles inoculated with sPMCA products developed clinical signs of TSE disease approximately 300 days prior to, and more consistently than, those inoculated with CWD prions from deer brain. Moreover, the deposition patterns and biochemical properties of protease-resistant form of PrP (PrPRES) in the brains of affected voles differed from those in cervidized transgenic (CerPrP) mice infected with CWD. In addition, voles inoculated orally with sPMCA products developed clinical signs of TSE and were positive for PrPRES deposition, whereas those inoculated orally with deer-origin CWD prions did not. These results demonstrate that transspecies sPMCA of CWD prions can enhance the infectivity and adapt the host range of CWD prions and thereby may be useful to assess determinants of prion species barriers.

  9. Prion-seeding activity in cerebrospinal fluid of deer with chronic wasting disease.

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    Nicholas J Haley

    Full Text Available Transmissible spongiform encephalopathies (TSEs, or prion diseases, are a uniformly fatal family of neurodegenerative diseases in mammals that includes chronic wasting disease (CWD of cervids. The early and ante-mortem identification of TSE-infected individuals using conventional western blotting or immunohistochemistry (IHC has proven difficult, as the levels of infectious prions in readily obtainable samples, including blood and bodily fluids, are typically beyond the limits of detection. The development of amplification-based seeding assays has been instrumental in the detection of low levels of infectious prions in clinical samples. In the present study, we evaluated the cerebrospinal fluid (CSF of CWD-exposed (n=44 and naïve (n=4 deer (n=48 total for CWD prions (PrP(d using two amplification assays: serial protein misfolding cyclic amplification with polytetrafluoroethylene beads (sPMCAb and real-time quaking induced conversion (RT-QuIC employing a truncated Syrian hamster recombinant protein substrate. Samples were evaluated blindly in parallel with appropriate positive and negative controls. Results from amplification assays were compared to one another and to obex immunohistochemistry, and were correlated to available clinical histories including CWD inoculum source (e.g. saliva, blood, genotype, survival period, and duration of clinical signs. We found that both sPMCAb and RT-QuIC were capable of amplifying CWD prions from cervid CSF, and results correlated well with one another. Prion seeding activity in either assay was observed in approximately 50% of deer with PrP(d detected by IHC in the obex region of the brain. Important predictors of amplification included duration of clinical signs and time of first tonsil biopsy positive results, and ultimately the levels of PrP(d identified in the obex by IHC. Based on our findings, we expect that both sPMCAb and RT-QuIC may prove to be useful detection assays for the detection of prions in

  10. Peroxymonosulfate Rapidly Inactivates the Disease-Associated Prion Protein.

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    Chesney, Alexandra R; Booth, Clarissa J; Lietz, Christopher B; Li, Lingjun; Pedersen, Joel A

    2016-07-01

    Prions, the etiological agents in transmissible spongiform encephalopathies, exhibit remarkable resistance to most methods of inactivation that are effective against conventional pathogens. Prions are composed of pathogenic conformers of the prion protein (PrP(TSE)). Some prion diseases are transmitted, in part, through environmental routes. The recalcitrance of prions to inactivation may lead to a persistent reservoir of infectivity that contributes to the environmental maintenance of epizootics. At present, few methods exist to remediate prion-contaminated land surfaces. Here we conducted a proof-of-principle study to examine the ability of peroxymonosulfate to degrade PrP(TSE). We find that peroxymonosulfate rapidly degrades PrP(TSE) from two species. Transition-metal-catalyzed decomposition of peroxymonosulfate to produce sulfate radicals appears to enhance degradation. We further demonstrate that exposure to peroxymonosulfate significantly reduced PrP(C) to PrP(TSE) converting ability as measured by protein misfolding cyclic amplification, used as a proxy for infectivity. Liquid chromatography-tandem mass spectrometry revealed that exposure to peroxymonosulfate results in oxidative modifications to methionine and tryptophan residues. This study indicates that peroxymonosulfate may hold promise for decontamination of prion-contaminated surfaces. PMID:27247993

  11. Effective gene therapy in a mouse model of prion diseases.

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    Karine Toupet

    Full Text Available Classical drug therapies against prion diseases have encountered serious difficulties. It has become urgent to develop radically different therapeutic strategies. Previously, we showed that VSV-G pseudotyped FIV derived vectors carrying dominant negative mutants of the PrP gene are efficient to inhibit prion replication in chronically prion-infected cells. Besides, they can transduce neurons and cells of the lymphoreticular system, highlighting their potential use in gene therapy approaches. Here, we used lentiviral gene transfer to deliver PrPQ167R virions possessing anti-prion properties to analyse their efficiency in vivo. Since treatment for prion diseases is initiated belatedly in human patients, we focused on the development of a curative therapeutic protocol targeting the late stage of the disease, either at 35 or 105 days post-infection (d.p.i. with prions. We observed a prolongation in the lifespan of the treated mice that prompted us to develop a system of cannula implantation into the brain of prion-infected mice. Chronic injections of PrPQ167R virions were done at 80 and 95 d.p.i. After only two injections, survival of the treated mice was extended by 30 days (20%, accompanied by substantial improvement in behaviour. This delay was correlated with: (i a strong reduction of spongiosis in the ipsilateral side of the brain by comparison with the contralateral side; and (ii a remarkable decrease in astrocytic gliosis in the whole brain. These results suggest that chronic injections of dominant negative lentiviral vectors into the brain, may be a promising approach for a curative treatment of prion diseases.

  12. Inherited prion disease A117V is not simply a proteinopathy but produces prions transmissible to transgenic mice expressing homologous prion protein.

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    Emmanuel A Asante

    Full Text Available Prions are infectious agents causing fatal neurodegenerative diseases of humans and animals. In humans, these have sporadic, acquired and inherited aetiologies. The inherited prion diseases are caused by one of over 30 coding mutations in the human prion protein (PrP gene (PRNP and many of these generate infectious prions as evidenced by their experimental transmissibility by inoculation to laboratory animals. However, some, and in particular an extensively studied type of Gerstmann-Sträussler-Scheinker syndrome (GSS caused by a PRNP A117V mutation, are thought not to generate infectious prions and instead constitute prion proteinopathies with a quite distinct pathogenetic mechanism. Multiple attempts to transmit A117V GSS have been unsuccessful and typical protease-resistant PrP (PrP(Sc, pathognomonic of prion disease, is not detected in brain. Pathogenesis is instead attributed to production of an aberrant topological form of PrP, C-terminal transmembrane PrP ((CtmPrP. Barriers to transmission of prion strains from one species to another appear to relate to structural compatibility of PrP in host and inoculum and we have therefore produced transgenic mice expressing human 117V PrP. We found that brain tissue from GSS A117V patients did transmit disease to these mice and both the neuropathological features of prion disease and presence of PrP(Sc was demonstrated in the brains of recipient transgenic mice. This PrP(Sc rapidly degraded during laboratory analysis, suggesting that the difficulty in its detection in patients with GSS A117V could relate to post-mortem proteolysis. We conclude that GSS A117V is indeed a prion disease although the relative contributions of (CtmPrP and prion propagation in neurodegeneration and their pathogenetic interaction remains to be established.

  13. Identification of Major Signaling Pathways in Prion Disease Progression Using Network Analysis.

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    Newaz, Khalique; Sriram, K; Bera, Debajyoti

    2015-01-01

    Prion diseases are transmissible neurodegenerative diseases that arise due to conformational change of normal, cellular prion protein (PrPC) to protease-resistant isofrom (rPrPSc). Deposition of misfolded PrpSc proteins leads to an alteration of many signaling pathways that includes immunological and apoptotic pathways. As a result, this culminates in the dysfunction and death of neuronal cells. Earlier works on transcriptomic studies have revealed some affected pathways, but it is not clear which is (are) the prime network pathway(s) that change during the disease progression and how these pathways are involved in crosstalks with each other from the time of incubation to clinical death. We perform network analysis on large-scale transcriptomic data of differentially expressed genes obtained from whole brain in six different mouse strain-prion strain combination models to determine the pathways involved in prion diseases, and to understand the role of crosstalks in disease propagation. We employ a notion of differential network centrality measures on protein interaction networks to identify the potential biological pathways involved. We also propose a crosstalk ranking method based on dynamic protein interaction networks to identify the core network elements involved in crosstalk with different pathways. We identify 148 DEGs (differentially expressed genes) potentially related to the prion disease progression. Functional association of the identified genes implicates a strong involvement of immunological pathways. We extract a bow-tie structure that is potentially dysregulated in prion disease. We also propose an ODE model for the bow-tie network. Predictions related to diseased condition suggests the downregulation of the core signaling elements (PI3Ks and AKTs) of the bow-tie network. In this work, we show using transcriptomic data that the neuronal dysfunction in prion disease is strongly related to the immunological pathways. We conclude that these

  14. Identification of Major Signaling Pathways in Prion Disease Progression Using Network Analysis.

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    Khalique Newaz

    Full Text Available Prion diseases are transmissible neurodegenerative diseases that arise due to conformational change of normal, cellular prion protein (PrPC to protease-resistant isofrom (rPrPSc. Deposition of misfolded PrpSc proteins leads to an alteration of many signaling pathways that includes immunological and apoptotic pathways. As a result, this culminates in the dysfunction and death of neuronal cells. Earlier works on transcriptomic studies have revealed some affected pathways, but it is not clear which is (are the prime network pathway(s that change during the disease progression and how these pathways are involved in crosstalks with each other from the time of incubation to clinical death. We perform network analysis on large-scale transcriptomic data of differentially expressed genes obtained from whole brain in six different mouse strain-prion strain combination models to determine the pathways involved in prion diseases, and to understand the role of crosstalks in disease propagation. We employ a notion of differential network centrality measures on protein interaction networks to identify the potential biological pathways involved. We also propose a crosstalk ranking method based on dynamic protein interaction networks to identify the core network elements involved in crosstalk with different pathways. We identify 148 DEGs (differentially expressed genes potentially related to the prion disease progression. Functional association of the identified genes implicates a strong involvement of immunological pathways. We extract a bow-tie structure that is potentially dysregulated in prion disease. We also propose an ODE model for the bow-tie network. Predictions related to diseased condition suggests the downregulation of the core signaling elements (PI3Ks and AKTs of the bow-tie network. In this work, we show using transcriptomic data that the neuronal dysfunction in prion disease is strongly related to the immunological pathways. We conclude that

  15. Kuru prions and sporadic Creutzfeldt-Jakob disease prions have equivalent transmission properties in transgenic and wild-type mice

    OpenAIRE

    Wadsworth, J D F; Joiner, S; Linehan, J M; Desbruslais, M.; Fox, K; Cooper, S.; Cronier, S.; Asante, E. A.; Mead, S.; Brandner, S; Hill, A. F.; Collinge, J.

    2008-01-01

    Kuru provides our principal experience of an epidemic human prion disease and primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. Kuru was transmitted by the practice of consuming dead relatives as a mark of respect and mourning (transumption). To date, detailed information of the prion strain type propagated in kuru has been lacking. Here, we directly compare the transmission properties of kuru prions with sporadic, iatrogenic, and variant Creutzfeldt–J...

  16. Peripheral prion disease pathogenesis is unaltered in the absence of sialoadhesin (Siglec-1/CD169)

    OpenAIRE

    Bradford, Barry; Crocker, P R; Mabbott, Neil

    2014-01-01

    Prions are a unique group of pathogens, which are considered to comprise solely of an abnormally folded isoform of the cellular prion protein. The accumulation and replication of prions within secondary lymphoid organs is important for their efficient spread from the periphery to the brain where they ultimately cause neurodegeneration and death. Mononuclear phagocytes (MNP) play key roles in prion disease pathogenesis. Some MNP appear to facilitate the propagation of prions to and within lymp...

  17. Complement protein C3 exacerbates prion disease in a mouse model of chronic wasting disease.

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    Michel, Brady; Ferguson, Adam; Johnson, Theodore; Bender, Heather; Meyerett-Reid, Crystal; Wyckoff, A Christy; Pulford, Bruce; Telling, Glenn C; Zabel, Mark D

    2013-12-01

    Accumulating evidence shows a critical role of the complement system in facilitating attachment of prions to both B cells and follicular dendritic cells and assisting in prion replication. Complement activation intensifies disease in prion-infected animals, and elimination of complement components inhibits prion accumulation, replication and pathogenesis. Chronic wasting disease (CWD) is a highly infectious prion disease of captive and free-ranging cervid populations that utilizes the complement system for efficient peripheral prion replication and most likely efficient horizontal transmission. Here we show that complete genetic or transient pharmacological depletion of C3 prolongs incubation times and significantly delays splenic accumulation in a CWD transgenic mouse model. Using a semi-quantitative prion amplification scoring system we show that C3 impacts disease progression in the early stages of disease by slowing the rate of prion accumulation and/or replication. The delayed kinetics in prion replication correlate with delayed disease kinetics in mice deficient in C3. Taken together, these data support a critical role of C3 in peripheral CWD prion pathogenesis. PMID:24038599

  18. Yeast prions: structure, biology, and prion-handling systems.

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    Wickner, Reed B; Shewmaker, Frank P; Bateman, David A; Edskes, Herman K; Gorkovskiy, Anton; Dayani, Yaron; Bezsonov, Evgeny E

    2015-03-01

    A prion is an infectious protein horizontally transmitting a disease or trait without a required nucleic acid. Yeast and fungal prions are nonchromosomal genes composed of protein, generally an altered form of a protein that catalyzes the same alteration of the protein. Yeast prions are thus transmitted both vertically (as genes composed of protein) and horizontally (as infectious proteins, or prions). Formation of amyloids (linear ordered β-sheet-rich protein aggregates with β-strands perpendicular to the long axis of the filament) underlies most yeast and fungal prions, and a single prion protein can have any of several distinct self-propagating amyloid forms with different biological properties (prion variants). Here we review the mechanism of faithful templating of protein conformation, the biological roles of these prions, and their interactions with cellular chaperones, the Btn2 and Cur1 aggregate-handling systems, and other cellular factors governing prion generation and propagation. Human amyloidoses include the PrP-based prion conditions and many other, more common amyloid-based diseases, several of which show prion-like features. Yeast prions increasingly are serving as models for the understanding and treatment of many mammalian amyloidoses. Patients with different clinical pictures of the same amyloidosis may be the equivalent of yeasts with different prion variants.

  19. Prion disease resembling frontotemporal dementia and parkinsonism linked to chromosome 17

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    Nitrini Ricardo

    2001-01-01

    Full Text Available OBJECTIVE: To compare the clinical features of a familial prion disease with those of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17. BACKGROUND: Prion diseases are not usually considered in the differential diagnosis of FTDP-17, since familial Creutzfeldt-Jakob disease (CJD, the most common inherited prion disease, often manifests as a rapidly progressive dementia. Conversely, FTDP-17 usually has an insidious onset in the fifth decade, with abnormal behavior and parkinsonian features. METHOD: We present the clinical features of 12 patients from a family with CJD associated with a point mutation at codon 183 of the prion protein gene. RESULTS: The mean age at onset was 44.0 ± 3.7; the duration of the symptoms until death ranged from two to nine years. Behavioral disturbances were the predominant presenting symptoms. Nine patients were first seen by psychiatrists. Eight patients manifested parkinsonian signs. CONCLUSION: These clinical features bear a considerable resemblance to those described in FTDP-17.

  20. Crucial Role for Prion Protein Membrane Anchoring in the Neuroinvasion and Neural Spread of Prion Infection ▿

    OpenAIRE

    Klingeborn, Mikael; Race, Brent; Meade-White, Kimberly D.; Rosenke, Rebecca; Striebel, James F.; Chesebro, Bruce

    2010-01-01

    In nature prion diseases are usually transmitted by extracerebral prion infection, but clinical disease results only after invasion of the central nervous system (CNS). Prion protein (PrP), a host-encoded glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein, is necessary for prion infection and disease. Here, we investigated the role of the anchoring of PrP on prion neuroinvasion by studying various inoculation routes in mice expressing either anchored or anchorless PrP. In contr...

  1. Porcine prion protein amyloid.

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    Hammarström, Per; Nyström, Sofie

    2015-01-01

    Mammalian prions are composed of misfolded aggregated prion protein (PrP) with amyloid-like features. Prions are zoonotic disease agents that infect a wide variety of mammalian species including humans. Mammals and by-products thereof which are frequently encountered in daily life are most important for human health. It is established that bovine prions (BSE) can infect humans while there is no such evidence for any other prion susceptible species in the human food chain (sheep, goat, elk, deer) and largely prion resistant species (pig) or susceptible and resistant pets (cat and dogs, respectively). PrPs from these species have been characterized using biochemistry, biophysics and neurobiology. Recently we studied PrPs from several mammals in vitro and found evidence for generic amyloidogenicity as well as cross-seeding fibril formation activity of all PrPs on the human PrP sequence regardless if the original species was resistant or susceptible to prion disease. Porcine PrP amyloidogenicity was among the studied. Experimentally inoculated pigs as well as transgenic mouse lines overexpressing porcine PrP have, in the past, been used to investigate the possibility of prion transmission in pigs. The pig is a species with extraordinarily wide use within human daily life with over a billion pigs harvested for human consumption each year. Here we discuss the possibility that the largely prion disease resistant pig can be a clinically silent carrier of replicating prions.

  2. Prions

    Directory of Open Access Journals (Sweden)

    J. M. Godoy

    1991-06-01

    Full Text Available Os autores se propõem a revisar alguns aspectos básicos sobre os prions, alertando sobre a possível participação destes na etiologia de algumas enfermidades degenerativas do sistema nervoso.

  3. [Prion neuroinfections].

    Science.gov (United States)

    Tichý, J

    2004-01-01

    Prion neuroinfections represent an emergent problem namely after the epidemic brake out of the bovine spongiform encephalopathies, which culminated in 1993. Isolated cases can still emerge. The next case was the discovery of a new variant of Creutzfeldt-Jakob disease in the comparatively young persons with proved alimentary infection route--about 140 cases has been described. Physiological prions are glycoproteins, affixed to the rafts of cell membranes (namely in neurons) by glycosylphosphatidylinositol anchor. They act as signalling molecules and participate in the cooper metabolism. Despite the intensive study in many prestigious laboratories, the way how the pathogenic isoform of prions, given by the prevalence of beta-conformations in the polypeptide chain develops has not been proved yet. Pathogenic isoforms are formed intracellulary after the precedent endocytosis. Aggregations of abnormal prion molecules build up prion amyloid deposits in the form of fibrils or plaques. The loss of neurons brings about the neurological symptoms, which are not directly related to the amounts of amyloid deposits. Characteristic findings of spongiosis and the immunohistochemical evidence of protease-resistant prions belong to the only reliable tests. Reliable intravital test in the blood or urine is not yet available. All forms of human and animal transmissible spongiform encephalopathies develop only in genetically sensitive individuals. A brief overview of clinical forms and some biochemical and genetic aspects of the disease are given.

  4. Accumulation of abnormal prion protein in mice infected with Creutzfeldt-Jakob disease via intraperitoneal route: a sequential study.

    OpenAIRE

    Muramoto, T; Kitamoto, T.; Tateishi, J.; Goto, I.

    1993-01-01

    We immunohistochemically studied the location of abnormal prion protein in the central nervous system and visceral organs at the clinical and preclinical stages of mice infected with Creutzfeldt-Jakob disease via intraperitoneal route. Abnormal prion protein was diffusely distributed in the central nervous system. The sequential study showed that its stainings were first detected 120 days after inoculation, were found in all mice after 180 days, and were the most intense and widespread after ...

  5. Role of autophagy in prion protein-induced neurodegenerative diseases

    Institute of Scientific and Technical Information of China (English)

    Hao Yao; Deming Zhao; Sher Hayat Khan; Lifeng Yang

    2013-01-01

    Prion diseases,characterized by spongiform degeneration and the accumulation of misfolded and aggregated PrPSc in the central nervous system,are one of fatal neurodegenerative and infectious disorders of humans and animals.In earlier studies,autophagy vacuoles in neurons were frequently observed in neurodegenerative diseases such as Alzheimer's,Parkinson's,and Huntington's diseases as well as prion diseases.Autophagy is a highly conserved homeostatic process by which several cytoplasmic components (proteins or organelles) are sequestered in a doublemembrane-bound vesicle termed 'autophagosome' and degraded upon their fusion with lysosome.The pathway of intercellular self-digestion at basal physiological levels is indispensable for maintaining the healthy status of tissues and organs.In case of prion infection,increasing evidence indicates that autophagy has a crucial ability of eliminating pathological PrPSc accumulated within neurons.In contrast,autophagy dysfunction in affected neurons may contribute to the formation of spongiform changes.In this review,we summarized recent findings about the effect of mammalian autophagy in neurodegenerative disorders,particularly in prion diseases.We also summarized the therapeutic potential of some small molecules (such as lithium,rapamycin,Sirtuin 1 and resveratrol) targets to mitigate such diseases on brain function.Furthermore,we discussed the controversial role of autophagy,whether it mediates neuronal toxicity or serves a protective function in neurodegenerative disorders.

  6. Defining the Conformational Features of Anchorless, Poorly Neuroinvasive Prions

    OpenAIRE

    Cyrus Bett; Kurt, Tim D.; Melanie Lucero; Margarita Trejo; Rozemuller, Annemieke J.; Qingzhong Kong; K. Peter R. Nilsson; Eliezer Masliah; Oldstone, Michael B.; Sigurdson, Christina J.

    2013-01-01

    Infectious prions cause diverse clinical signs and form an extraordinary range of structures, from amorphous aggregates to fibrils. How the conformation of a prion dictates the disease phenotype remains unclear. Mice expressing GPI-anchorless or GPI-anchored prion protein exposed to the same infectious prion develop fibrillar or nonfibrillar aggregates, respectively, and show a striking divergence in the disease pathogenesis. To better understand how a prion's physical properties govern the p...

  7. Metabolic patterns in prion diseases: an FDG PET voxel-based analysis

    International Nuclear Information System (INIS)

    Clinical diagnosis of human prion diseases can be challenging since symptoms are common to other disorders associated with rapidly progressive dementia. In this context, 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) might be a useful complementary tool. The aim of this study was to determine the metabolic pattern in human prion diseases, particularly sporadic Creutzfeldt-Jakob disease (sCJD), the new variant of Creutzfeldt-Jakob disease (vCJD) and fatal familial insomnia (FFI). We retrospectively studied 17 patients with a definitive, probable or possible prion disease who underwent FDG PET in our institution. Of these patients, 12 were diagnosed as sCJD (9 definitive, 2 probable and 1 possible), 1 was diagnosed as definitive vCJD and 4 were diagnosed as definitive FFI. The hypometabolic pattern of each individual and comparisons across the groups of subjects (control subjects, sCJD and FFI) were evaluated using a voxel-based analysis. The sCJD group exhibited a pattern of hypometabolism that affected both subcortical (bilateral caudate, thalamus) and cortical (frontal cortex) structures, while the FFI group only presented a slight hypometabolism in the thalamus. Individual analysis demonstrated a considerable variability of metabolic patterns among patients, with the thalamus and basal ganglia the most frequently affected areas, combined in some cases with frontal and temporal hypometabolism. Patients with a prion disease exhibit a characteristic pattern of brain metabolism presentation in FDG PET imaging. Consequently, in patients with rapidly progressive cognitive impairment, the detection of these patterns in the FDG PET study could orient the diagnosis to a prion disease. (orig.)

  8. Metabolic patterns in prion diseases: an FDG PET voxel-based analysis

    Energy Technology Data Exchange (ETDEWEB)

    Prieto, Elena; Dominguez-Prado, Ines; Jesus Ribelles, Maria; Arbizu, Javier [Clinica Universidad de Navarra, Nuclear Medicine Department, Pamplona (Spain); Riverol, Mario; Ortega-Cubero, Sara; Rosario Luquin, Maria; Castro, Purificacion de [Clinica Universidad de Navarra, Neurology Department, Pamplona (Spain)

    2015-09-15

    Clinical diagnosis of human prion diseases can be challenging since symptoms are common to other disorders associated with rapidly progressive dementia. In this context, {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography (PET) might be a useful complementary tool. The aim of this study was to determine the metabolic pattern in human prion diseases, particularly sporadic Creutzfeldt-Jakob disease (sCJD), the new variant of Creutzfeldt-Jakob disease (vCJD) and fatal familial insomnia (FFI). We retrospectively studied 17 patients with a definitive, probable or possible prion disease who underwent FDG PET in our institution. Of these patients, 12 were diagnosed as sCJD (9 definitive, 2 probable and 1 possible), 1 was diagnosed as definitive vCJD and 4 were diagnosed as definitive FFI. The hypometabolic pattern of each individual and comparisons across the groups of subjects (control subjects, sCJD and FFI) were evaluated using a voxel-based analysis. The sCJD group exhibited a pattern of hypometabolism that affected both subcortical (bilateral caudate, thalamus) and cortical (frontal cortex) structures, while the FFI group only presented a slight hypometabolism in the thalamus. Individual analysis demonstrated a considerable variability of metabolic patterns among patients, with the thalamus and basal ganglia the most frequently affected areas, combined in some cases with frontal and temporal hypometabolism. Patients with a prion disease exhibit a characteristic pattern of brain metabolism presentation in FDG PET imaging. Consequently, in patients with rapidly progressive cognitive impairment, the detection of these patterns in the FDG PET study could orient the diagnosis to a prion disease. (orig.)

  9. Presence of voltage-gated potassium channel complex antibody in a case of genetic prion disease

    OpenAIRE

    Jammoul, Adham; Lederman, Richard J; Tavee, Jinny; Li, Yuebing

    2014-01-01

    Voltage-gated potassium channel (VGKC) complex antibody-mediated encephalitis is a recently recognised entity which has been reported to mimic the clinical presentation of Creutzfeldt-Jakob disease (CJD). Testing for the presence of this neuronal surface autoantibody in patients presenting with subacute encephalopathy is therefore crucial as it may both revoke the bleak diagnosis of prion disease and allow institution of potentially life-saving immunotherapy. Tempering this optimistic view is...

  10. Double-Edge Sword of Sustained ROCK Activation in Prion Diseases through Neuritogenesis Defects and Prion Accumulation.

    Science.gov (United States)

    Alleaume-Butaux, Aurélie; Nicot, Simon; Pietri, Mathéa; Baudry, Anne; Dakowski, Caroline; Tixador, Philippe; Ardila-Osorio, Hector; Haeberlé, Anne-Marie; Bailly, Yannick; Peyrin, Jean-Michel; Launay, Jean-Marie; Kellermann, Odile; Schneider, Benoit

    2015-08-01

    In prion diseases, synapse dysfunction, axon retraction and loss of neuronal polarity precede neuronal death. The mechanisms driving such polarization defects, however, remain unclear. Here, we examined the contribution of RhoA-associated coiled-coil containing kinases (ROCK), key players in neuritogenesis, to prion diseases. We found that overactivation of ROCK signaling occurred in neuronal stem cells infected by pathogenic prions (PrPSc) and impaired the sprouting of neurites. In reconstructed networks of mature neurons, PrPSc-induced ROCK overactivation provoked synapse disconnection and dendrite/axon degeneration. This overactivation of ROCK also disturbed overall neurotransmitter-associated functions. Importantly, we demonstrated that beyond its impact on neuronal polarity ROCK overactivity favored the production of PrPSc through a ROCK-dependent control of 3-phosphoinositide-dependent kinase 1 (PDK1) activity. In non-infectious conditions, ROCK and PDK1 associated within a complex and ROCK phosphorylated PDK1, conferring basal activity to PDK1. In prion-infected neurons, exacerbated ROCK activity increased the pool of PDK1 molecules physically interacting with and phosphorylated by ROCK. ROCK-induced PDK1 overstimulation then canceled the neuroprotective α-cleavage of normal cellular prion protein PrPC by TACE α-secretase, which physiologically precludes PrPSc production. In prion-infected cells, inhibition of ROCK rescued neurite sprouting, preserved neuronal architecture, restored neuronal functions and reduced the amount of PrPSc. In mice challenged with prions, inhibition of ROCK also lowered brain PrPSc accumulation, reduced motor impairment and extended survival. We conclude that ROCK overactivation exerts a double detrimental effect in prion diseases by altering neuronal polarity and triggering PrPSc accumulation. Eventually ROCK emerges as therapeutic target to combat prion diseases. PMID:26241960

  11. Characterization of variant Creutzfeldt-Jakob disease prions in prion protein-humanized mice carrying distinct codon 129 genotypes.

    Science.gov (United States)

    Takeuchi, Atsuko; Kobayashi, Atsushi; Ironside, James W; Mohri, Shirou; Kitamoto, Tetsuyuki

    2013-07-26

    To date, all clinical variant Creutzfeldt-Jakob disease (vCJD) patients are homozygous for methionine at polymorphic codon 129 (129M/M) of the prion protein (PrP) gene. However, the appearance of asymptomatic secondary vCJD infection in individuals with a PRNP codon 129 genotype other than M/M and transmission studies using animal models have raised the concern that all humans might be susceptible to vCJD prions, especially via secondary infection. To reevaluate this possibility and to analyze in detail the transmission properties of vCJD prions to transgenic animals carrying distinct codon 129 genotype, we performed intracerebral inoculation of vCJD prions to humanized knock-in mice carrying all possible codon 129 genotypes (129M/M, 129M/V, or 129V/V). All humanized knock-in mouse lines were susceptible to vCJD infection, although the attack rate gradually decreased from 129M/M to 129M/V and to 129V/V. The amount of PrP deposition including florid/amyloid plaques in the brain also gradually decreased from 129M/M to 129M/V and to 129V/V. The biochemical properties of protease-resistant abnormal PrP in the brain and transmissibility of these humanized mouse-passaged vCJD prions upon subpassage into knock-in mice expressing bovine PrP were not affected by the codon 129 genotype. These results indicate that individuals with the 129V/V genotype may be more susceptible to secondary vCJD infection than expected and may lack the neuropathological characteristics observed in vCJD patients with the 129M/M genotype. Besides the molecular typing of protease-resistant PrP in the brain, transmission studies using knock-in mice carrying bovine PrP may aid the differential diagnosis of secondary vCJD infection, especially in individuals with the 129V/V genotype.

  12. Presence of voltage-gated potassium channel complex antibody in a case of genetic prion disease.

    Science.gov (United States)

    Jammoul, Adham; Lederman, Richard J; Tavee, Jinny; Li, Yuebing

    2014-06-05

    Voltage-gated potassium channel (VGKC) complex antibody-mediated encephalitis is a recently recognised entity which has been reported to mimic the clinical presentation of Creutzfeldt-Jakob disease (CJD). Testing for the presence of this neuronal surface autoantibody in patients presenting with subacute encephalopathy is therefore crucial as it may both revoke the bleak diagnosis of prion disease and allow institution of potentially life-saving immunotherapy. Tempering this optimistic view is the rare instance when a positive VGKC complex antibody titre occurs in a definite case of prion disease. We present a pathologically and genetically confirmed case of CJD with elevated serum VGKC complex antibody titres. This case highlights the importance of interpreting the result of a positive VGKC complex antibody with caution and in the context of the overall clinical manifestation.

  13. Resistance to chronic wasting disease in transgenic mice expressing a naturally occurring allelic variant of deer prion protein

    NARCIS (Netherlands)

    Meade-White, K.; Race, B.; Trifilo, M.; Bossers, A.; Favara, C.; Lacasse, R.; Miller, M.; Williams, E.; Oldstone, M.; Race, R.; Chesebro, B.

    2007-01-01

    Prion protein (PrP) is a required factor for susceptibility to transmissible spongiform encephalopathy or prion diseases. In transgenic mice, expression of prion protein (PrP) from another species often confers susceptibility to prion disease from that donor species. For example, expression of deer

  14. Coexistence of protease sensitive and resistant prion protein in 129VV homozygous sporadic Creutzfeldt–Jakob disease: a case report

    Directory of Open Access Journals (Sweden)

    Rodríguez-Martínez Ana B

    2012-10-01

    Full Text Available Abstract Introduction The coexistence of different molecular types of classical protease-resistant prion protein in the same individual have been described, however, the simultaneous finding of these with the recently described protease-sensitive variant or variably protease-sensitive prionopathy has, to the best of our knowledge, not yet been reported. Case presentation A 74-year-old Caucasian woman showed a sporadic Creutzfeldt–Jakob disease clinical phenotype with reactive depression, followed by cognitive impairment, akinetic-rigid Parkinsonism with pseudobulbar syndrome and gait impairment with motor apraxia, visuospatial disorientation, and evident frontal dysfunction features such as grasping, palmomental reflex and brisk perioral reflexes. She died at age 77. Neuropathological findings showed: spongiform change in the patient’s cerebral cortex, striatum, thalamus and molecular layer of the cerebellum with proteinase K-sensitive synaptic-like, dot-like or target-like prion protein deposition in the cortex, thalamus and striatum; proteinase K-resistant prion protein in the same regions; and elongated plaque-like proteinase K-resistant prion protein in the molecular layer of the cerebellum. Molecular analysis of prion protein after proteinase K digestion revealed decreased signal intensity in immunoblot, a ladder-like protein pattern, and a 71% reduction of PrPSc signal relative to non-digested material. Her cerebellum showed a 2A prion protein type largely resistant to proteinase K. Genotype of polymorphism at codon 129 was valine homozygous. Conclusion Molecular typing of prion protein along with clinical and neuropathological data revealed, to the best of our knowledge, the first case of the coexistence of different protease-sensitive prion proteins in the same patient in a rare case that did not fulfill the current clinical diagnostic criteria for either probable or possible sporadic Creutzfeldt–Jakob disease. This highlights the

  15. Copper and the Prion Protein: Methods, Structures, Function, and Disease

    Science.gov (United States)

    Millhauser, Glenn L.

    2007-05-01

    The transmissible spongiform encephalopathies (TSEs) arise from conversion of the membrane-bound prion protein from PrPC to PrPSc. Examples of the TSEs include mad cow disease, chronic wasting disease in deer and elk, scrapie in goats and sheep, and kuru and Creutzfeldt-Jakob disease in humans. Although the precise function of PrPC in healthy tissues is not known, recent research demonstrates that it binds Cu(II) in an unusual and highly conserved region of the protein termed the octarepeat domain. This review describes recent connections between copper and PrPC, with an emphasis on the electron paramagnetic resonance elucidation of the specific copper-binding sites, insights into PrPC function, and emerging connections between copper and prion disease.

  16. Historical overview of prion diseases: a view from afar.

    Science.gov (United States)

    Liberski, Pawel P

    2012-01-01

    The transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of neurodegenerative disorders which include kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and fatal familial insomnia in men, natural scrapie in sheep, goats and mufflons, transmissible mink encephalopathy in ranch-reared mink, chronic wasting disease of mule deer and elk, bovine spongiform encephalopathy or "mad cow disease" and its analogues in several exotic species of antelopes and wild felids in zoological gardens, and feline spongiform encephalopathy in domestic cats. This short review summarizes the history of the research to find the nature of the scrapie agent, especially as I have witnessed it unfolding before my eyes. I review the historical background of TSEs starting from the first description of scrapie in 1732. In 1957, the first prion disease in humans, kuru was described and its transmissibility was demonstrated in 1965 by seminal work of Gajdusek, Gibbs and colleagues, followed by transmission of CJD and then, GSS. In 1982, Stanley B. Prusiner formulated "prion hypothesis" which has dominated the field for the last 30 years. This theory had been recently extended to cover other neurodegenerations which are caused by misfolded proteins; these disease are called prionoids. PMID:22505359

  17. Genetic predictions of prion disease susceptibility in carnivore species based on variability of the prion gene coding region.

    Directory of Open Access Journals (Sweden)

    Paula Stewart

    Full Text Available Mammalian species vary widely in their apparent susceptibility to prion diseases. For example, several felid species developed prion disease (feline spongiform encephalopathy or FSE during the bovine spongiform encephalopathy (BSE epidemic in the United Kingdom, whereas no canine BSE cases were detected. Whether either of these or other groups of carnivore species can contract other prion diseases (e.g. chronic wasting disease or CWD remains an open question. Variation in the host-encoded prion protein (PrP(C largely explains observed disease susceptibility patterns within ruminant species, and may explain interspecies differences in susceptibility as well. We sequenced and compared the open reading frame of the PRNP gene encoding PrP(C protein from 609 animal samples comprising 29 species from 22 genera of the Order Carnivora; amongst these samples were 15 FSE cases. Our analysis revealed that FSE cases did not encode an identifiable disease-associated PrP polymorphism. However, all canid PrPs contained aspartic acid or glutamic acid at codon 163 which we propose provides a genetic basis for observed susceptibility differences between canids and felids. Among other carnivores studied, wolverine (Gulo gulo and pine marten (Martes martes were the only non-canid species to also express PrP-Asp163, which may impact on their prion diseases susceptibility. Populations of black bear (Ursus americanus and mountain lion (Puma concolor from Colorado showed little genetic variation in the PrP protein and no variants likely to be highly resistant to prions in general, suggesting that strain differences between BSE and CWD prions also may contribute to the limited apparent host range of the latter.

  18. Defining the conformational features of anchorless, poorly neuroinvasive prions.

    Directory of Open Access Journals (Sweden)

    Cyrus Bett

    Full Text Available Infectious prions cause diverse clinical signs and form an extraordinary range of structures, from amorphous aggregates to fibrils. How the conformation of a prion dictates the disease phenotype remains unclear. Mice expressing GPI-anchorless or GPI-anchored prion protein exposed to the same infectious prion develop fibrillar or nonfibrillar aggregates, respectively, and show a striking divergence in the disease pathogenesis. To better understand how a prion's physical properties govern the pathogenesis, infectious anchorless prions were passaged in mice expressing anchorless prion protein and the resulting prions were biochemically characterized. Serial passage of anchorless prions led to a significant decrease in the incubation period to terminal disease and altered the biochemical properties, consistent with a transmission barrier effect. After an intraperitoneal exposure, anchorless prions were only weakly neuroinvasive, as prion plaques rarely occurred in the brain yet were abundant in extracerebral sites such as heart and adipose tissue. Anchorless prions consistently showed very high stability in chaotropes or when heated in SDS, and were highly resistant to enzyme digestion. Consistent with the results in mice, anchorless prions from a human patient were also highly stable in chaotropes. These findings reveal that anchorless prions consist of fibrillar and highly stable conformers. The additional finding from our group and others that both anchorless and anchored prion fibrils are poorly neuroinvasive strengthens the hypothesis that a fibrillar prion structure impedes efficient CNS invasion.

  19. Atypical Scrapie Prions from Sheep and Lack of Disease in Transgenic Mice Overexpressing Human Prion Protein

    OpenAIRE

    Wadsworth, Jonathan D. F.; Joiner, Susan; Linehan, Jacqueline M; Balkema-Buschmann, Anne; Spiropoulos, John; Simmons, Marion M; Griffiths, Peter C; Martin H Groschup; Hope, James; Brandner, Sebastian; Asante, Emmanuel A.; Collinge, John

    2013-01-01

    Public and animal health controls to limit human exposure to animal prions are focused on bovine spongiform encephalopathy (BSE), but other prion strains in ruminants may also have zoonotic potential. One example is atypical/Nor98 scrapie, which evaded statutory diagnostic methods worldwide until the early 2000s. To investigate whether sheep infected with scrapie prions could be another source of infection, we inoculated transgenic mice that overexpressed human prion protein with brain tissue...

  20. Simulations of Oligomeric Intermediates in Prion Diseases

    CERN Document Server

    Mobley, D L; Singh, R R P; Kulkarni, R V; Slepoy, A; Mobley, David L.; Cox, Daniel L.; Singh, Rajiv R. P.; Kulkarni, Rahul V.; Slepoy, Alexander

    2003-01-01

    We extend our previous stochastic cellular automata based model for areal aggregation of prion proteins on neuronal surfaces. The new anisotropic model allow us to simulate both strong beta-sheet and weaker attachment bonds between proteins. Constraining binding directions allows us to generate aggregate structures with the hexagonal lattice symmetry found in recently observed in vitro experiments. We argue that these constraints on rules may correspond to underlying steric constraints on the aggregation process. We find that monomer dominated growth of the areal aggregate is too slow to account for some observed doubling time-to-incubation time ratios inferred from data, and so consider aggregation dominated by relatively stable but non-infectious oligomeric intermediates. We compare a kinetic theory analysis of oligomeric aggregation to spatially explicit simulations of the process. We find that with suitable rules for misfolding of oligomers, possibly due to water exclusion by the surrounding aggregate, th...

  1. Dendritic cells and oral transmission of prion diseases

    OpenAIRE

    MacPherson, GG; Huang, FP

    2004-01-01

    Abstract Transmissible spongiform encephalopathies (scrapie, BSE, Kuru) develop as central nervous system (CNS) diseases after long incubation periods, and many of which may arise following the consumption of infected material. The infectious agent is thought to be a misfolded form (scrapie associated PrP (PrPSc)) of a normal host protein (cellular isoform of PrP (PrPC)), which is relatively resistant to proteolytic degradation and which serves as a template, directing host prion protein (...

  2. Dendritic cells and oral transmission of prion diseases.

    Science.gov (United States)

    Huang, Fang-Ping; MacPherson, G Gordon

    2004-04-19

    Transmissible spongiform encephalopathies (scrapie, BSE, Kuru) develop as central nervous system (CNS) diseases after long incubation periods, and many of which may arise following the consumption of infected material. The infectious agent is thought to be a misfolded form (scrapie associated PrP (PrP(Sc))) of a normal host protein (cellular isoform of PrP (PrP(C))), which is relatively resistant to proteolytic degradation and which serves as a template, directing host prion protein (PrP) to accumulate in the misfolded form. Animal experiments have shown that CNS disease is preceded by a period in which the agent accumulates in secondary lymphoid organs (Peyer's patches (PP), lymph nodes, spleen), particularly follicular dendritic cells (FDCs) in the B cell areas of these organs. How the agent is transmitted from the intestinal lumen to the FDCs is largely unknown. Dendritic cells (DCs, cells quite distinct from FDCs) are cells that are specialised to acquire antigens from peripheral tissues and to transport them to secondary lymphoid organs for presentation to T and B lymphocytes. We have shown that DCs can acquire PrP(Sc) from the intestinal lumen and deliver it to mesenteric lymph nodes. In this review we discuss the different stages involved in the migration of PrP(Sc) from the intestine to FDCs and consider the different stages and barriers involved in this process. We conclude that transport of the causative agent, using PrP(Sc) as a biomarker, from the intestine to FDCs is a very inefficient process, which may help to account for the apparent low frequency of individuals who have consumed infected material that go on to develop clinical disease. PMID:15063597

  3. Retinal function and morphology are altered in cattle infected with the prion disease transmissible mink encephalopathy.

    Science.gov (United States)

    Smith, J D; Greenlee, J J; Hamir, A N; Richt, J A; Greenlee, M H West

    2009-09-01

    Transmissible spongiform encephalopathies (TSEs) are a group of diseases that result in progressive and invariably fatal neurologic disease in both animals and humans. TSEs are characterized by the accumulation of an abnormal protease-resistant form of the prion protein in the central nervous system. Transmission of infectious TSEs is believed to occur via ingestion of prion protein-contaminated material. This material is also involved in the transmission of bovine spongiform encephalopathy ("mad cow disease") to humans, which resulted in the variant form of Creutzfeldt-Jakob disease. Abnormal prion protein has been reported in the retina of TSE-affected cattle, but despite these observations, the specific effect of abnormal prion protein on retinal morphology and function has not been assessed. The objective of this study was to identify and characterize potential functional and morphologic abnormalities in the retinas of cattle infected with a bovine-adapted isolate of transmissible mink encephalopathy. We used electroretinography and immunohistochemistry to examine retinas from 10 noninoculated and 5 transmissible mink encephalopathy-inoculated adult Holstein steers. Here we show altered retinal function, as evidenced by prolonged implicit time of the electroretinogram b-wave, in transmissible mink encephalopathy-infected cattle before the onset of clinical illness. We also demonstrate disruption of rod bipolar cell synaptic terminals, indicated by decreased immunoreactivity for the alpha isoform of protein kinase C and vesicular glutamate transporter 1, and activation of Müller glia, as evidenced by increased glial fibrillary acidic protein and glutamine synthetase expression, in the retinas of these cattle at the time of euthanasia due to clinical deterioration. This is the first study to identify both functional and morphologic alterations in the retinas of TSE-infected cattle. Our results support future efforts to focus on the retina for the development of

  4. Copper and the Prion Protein: Methods, Structures, Function, and Disease

    OpenAIRE

    Millhauser, Glenn L.

    2007-01-01

    The transmissible spongiform encephalopathies (TSEs) arise from conversion of the membrane-bound prion protein from PrPC to PrPSc. Examples of the TSEs include mad cow disease, chronic wasting disease in deer and elk, scrapie in goats and sheep, and kuru and Creutzfeldt-Jakob disease in humans. Although the precise function of PrPC in healthy tissues is not known, recent research demonstrates that it binds Cu(II) in an unusual and highly conserved region of the protein termed the octarepeat d...

  5. Searching for Factors that Distinguish Disease-Prone and Disease-Resistant Prions via Sequence Analysis

    Directory of Open Access Journals (Sweden)

    Lukasz Kurgan

    2008-01-01

    Full Text Available The exact mechanisms of prion misfolding and factors that predispose an individual to prion diseases are largely unknown. Our approach to identifying candidate factors in-silico relies on contrasting the C-terminal domain of PrPC sequences from two groups of vertebrate species: those that have been found to suffer from prion diseases, and those that have not. We propose that any significant differences between the two groups are candidate factors that may predispose individuals to develop prion disease, which should be further analyzed by wet-lab investigations. Using an array of computational methods we identified possible point mutations that could predispose PrPC to misfold into PrPSc. Our results include confirmatory findings such as the V210I mutation, and new findings including P137M, G142D, G142N, D144P, K185T, V189I, H187Y and T191P mutations, which could impact structural stability. We also propose new hypotheses that give insights into the stability of helix-2 and -3. These include destabilizing effects of Histidine and T188-T193 segment in helix-2 in the disease-prone prions, and a stabilizing effect of Leucine on helix-3 in the disease-resistant prions.

  6. The human prion diseases. A review with special emphasis on new variant CJD and comments on surveillance.

    LENUS (Irish Health Repository)

    Keohane, C

    2012-02-03

    The transmissible spongiform encephalopathies or prion diseases represent a new group of diseases with unique clinical and neuropathological features, the transmission of which is both genetic and infectious. The responsible agent is unconventional and appears to be largely composed of a glycoprotein, the prion protein PrP. This is normally present on different cells. In prion diseases, it becomes converted to the pathogenic form PrPres which is resistant to proteinase and accumulates within the brain and this process is accompanied by the development of spongiform change, gliosis and neuronal loss. The human prion diseases include Kuru a progressive cerebellar degeneration with late dementia affecting Fore tribes in New-Guinea, now almost extinct, regarded as being related to cannibalism. Creutzfeldt-Jakob disease is the more frequent human prion disease. Its incidence is approximately one case per million per year. Four variants are now recognized: sporadic, familial, iatrogenic and the new variant. The latter represents a distinct clinico-pathological entity. It is now widely accepted that it is due to the same agent responsible for Bovine Spongiform Encephalopathy in cattle. Gerstmann-Straussler-Scheinker disease is a very rare inherited disorder due to a number of different mutations in the PRP gene, characterized by abundant deposits of plaque PrPres in the cerebral grey matter. Fatal familial insomnia is another inherited disorder due to a mutation at codon 178 of the PRP gene associated with methionine on codon 129 of the mutant allele. The main neuropathological change is neuronal loss in the thalamus with little or no spongiosis and usually no PrPres deposition. Following the emergence of new variant CJD in 1996, surveillance of all forms of prion diseases has been now been actively introduced in many European nations in order to determine the true incidence and geographic distribution of these rare disorders in humans.

  7. Transcriptional modulation in a leukocyte-depleted splenic cell population during prion disease.

    Science.gov (United States)

    Huzarewich, Rhiannon L C H; Medina, Sarah; Robertson, Catherine; Parchaliuk, Debra; Booth, Stephanie A

    2011-01-01

    Prion replication in the periphery precedes neuroinvasion in many experimental rodent scrapie models, and in natural sheep scrapie and chronic wasting disease (CWD) in cervids. Prions propagate in the germinal centers of secondary lymphoid organs and are strongly associated with follicular dendritic cells (FDC) and possibly circulating dendritic cells and macrophages. Given the importance of lymphoid organs in prion disease transmission and pathogenesis, gene expression studies may reveal host factors or biological pathways related to prion replication and accumulation. A procedure was developed to enrich for FDC, dendritic cells, and macrophages prior to the investigation of transcriptional alterations in murine splenic cells during prion pathogenesis. In total, 1753 transcripts exhibited fold changes greater than three (false discovery rates less than 2%) in this population isolated from spleens of prion-infected versus uninfected mice. The gene for the small leucine-rich proteoglycan decorin (DCN) was one of the genes most overexpressed in infected mice, and the splenic protein levels mirrored this in mice infected with scrapie as well as bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD). A number of groups of functionally related genes were also significantly decreased in infected spleens. These included genes related to iron metabolism and homeostasis, pathways that have also been implicated in prion pathogenesis in the brain. These gene expression alterations provide insights into the molecular mechanisms underlying prion disease pathogenesis and may serve as a pool of potential surrogate markers for the early detection and diagnosis of some prion diseases. PMID:22043911

  8. Human Tonsil-Derived Follicular Dendritic-Like Cells are Refractory to Human Prion Infection in Vitro and Traffic Disease-Associated Prion Protein to Lysosomes

    OpenAIRE

    Krejciova, Zuzana; De Sousa, Paul; Manson, Jean; Ironside, James W.; Mark W Head

    2014-01-01

    The molecular mechanisms involved in human cellular susceptibility to prion infection remain poorly defined. This is due, in part, to the absence of any well characterized and relevant cultured human cells susceptible to infection with human prions, such as those involved in Creutzfeldt-Jakob disease. In variant Creutzfeldt-Jakob disease, prion replication is thought to occur first in the lymphoreticular system and then spread into the brain. We have, therefore, examined the susceptibility of...

  9. Infectious Prions in the Saliva and Blood of Deer with Chronic Wasting Disease

    Science.gov (United States)

    Mathiason, Candace K.; Powers, Jenny G.; Dahmes, Sallie J.; Osborn, David A.; Miller, Karl V.; Warren, Robert J.; Mason, Gary L.; Hays, Sheila A.; Hayes-Klug, Jeanette; Seelig, Davis M.; Wild, Margaret A.; Wolfe, Lisa L.; Spraker, Terry R.; Miller, Michael W.; Sigurdson, Christina J.; Telling, Glenn C.; Hoover, Edward A.

    2006-10-01

    A critical concern in the transmission of prion diseases, including chronic wasting disease (CWD) of cervids, is the potential presence of prions in body fluids. To address this issue directly, we exposed cohorts of CWD-naïve deer to saliva, blood, or urine and feces from CWD-positive deer. We found infectious prions capable of transmitting CWD in saliva (by the oral route) and in blood (by transfusion). The results help to explain the facile transmission of CWD among cervids and prompt caution concerning contact with body fluids in prion infections.

  10. Review on prion diseases in animals with emphasis to Bovine Spongiform Encephalopathy

    Directory of Open Access Journals (Sweden)

    Rajender P. Gupta

    Full Text Available Prion diseases are known as Transmissible Spongiform Encephalopathies (TSE. These are degenerative brain disorders characterized by tiny microscopic holes that give the brain 'spongy' appearance. The causative agent is proteinaceous infective particle called prion. Prion diseases affect a variety of mammals including humans. The disease is transmitted by contaminated food or feed containing prion protein. In animals the diseases caused by prions are Scrapie, Bovine Spongiform Encephalopathy (BSE, Transmissible Mink Encephalopathy (TME, Chronic Wasting Disease (CWD, Feline Spongiform Encephalopathy (FSE and exotic Engulate Encephalopathy (EUE. Currently the only reliable test is histo-pathological examination of tissues. Control measures are surveillance, culling sick animals and banning specified risk materials. In India no case of BSE has been reported so far but the disease warrants constant monitoring and surveillance if once introduced or imported would be a herculean task to eradicate it. [Vet. World 2012; 5(7.000: 443-448

  11. Familial Creutzfeldt-Jakob disease associated with a point mutation at codon 210 of the prion protein gene

    Directory of Open Access Journals (Sweden)

    Huang Nancy

    2001-01-01

    Full Text Available Creutzfeldt-Jakob disease (CJD, the most known human prion disease, is usually sporadic but approximately 15% of the cases are familial. To date, seven CJD cases with codon 210 mutation (GTT to ATT have been reported in the literature. We describe a case of a 57 year-old woman who presented gait disturbances and rapidly progressive dementia, leading to death four months after onset. Electroencephalogram revealed periodic activity, diffusion-weighted magnetic resonance imaging showed hypersignal in basal ganglia, and test for 14-3-3 protein was strongly positive in the CSF. The complete prion protein gene coding region was sequenced after PCR amplification, showing a point mutation in codon 210. This is the first case of CJD with codon 210 mutation diagnosed in Brazil. We emphasize the role of genetic search for prion protein gene mutation, even in patients presenting clinical features resembling sporadic CJD.

  12. Glycoform-selective prion formation in sporadic and familial forms of prion disease.

    Directory of Open Access Journals (Sweden)

    Xiangzhu Xiao

    Full Text Available The four glycoforms of the cellular prion protein (PrP(C variably glycosylated at the two N-linked glycosylation sites are converted into their pathological forms (PrP(Sc in most cases of sporadic prion diseases. However, a prominent molecular characteristic of PrP(Sc in the recently identified variably protease-sensitive prionopathy (VPSPr is the absence of a diglycosylated form, also notable in familial Creutzfeldt-Jakob disease (fCJD, which is linked to mutations in PrP either from Val to Ile at residue 180 (fCJD(V180I or from Thr to Ala at residue 183 (fCJD(T183A. Here we report that fCJD(V180I, but not fCJD(T183A, exhibits a proteinase K (PK-resistant PrP (PrP(res that is markedly similar to that observed in VPSPr, which exhibits a five-step ladder-like electrophoretic profile, a molecular hallmark of VPSPr. Remarkably, the absence of the diglycosylated PrP(res species in both fCJD(V180I and VPSPr is likewise attributable to the absence of PrP(res glycosylated at the first N-linked glycosylation site at residue 181, as in fCJD(T183A. In contrast to fCJD(T183A, both VPSPr and fCJD(V180I exhibit glycosylation at residue 181 on di- and monoglycosylated (mono181 PrP prior to PK-treatment. Furthermore, PrP(V180I with a typical glycoform profile from cultured cells generates detectable PrP(res that also contains the diglycosylated PrP in addition to mono- and unglycosylated forms upon PK-treatment. Taken together, our current in vivo and in vitro studies indicate that sporadic VPSPr and familial CJD(V180I share a unique glycoform-selective prion formation pathway in which the conversion of diglycosylated and mono181 PrP(C to PrP(Sc is inhibited, probably by a dominant-negative effect, or by other co-factors.

  13. Detection of type 1 prion protein in variant Creutzfeldt-Jakob disease

    NARCIS (Netherlands)

    Yull, H.M.; Ritchie, D.L.; Langeveld, J.P.M.; Zijderveld, van F.G.; Bruce, M.E.; Ironside, J.W.; Head, M.W.

    2006-01-01

    Molecular typing of the abnormal form of the prion protein (PrPSc) has come to be regarded as a powerful tool in the investigation of the prion diseases. All evidence thus far presented indicates a single PrPSc molecular type in variant Creutzfeldt-Jakob disease (termed type 2B), presumably resultin

  14. [Doctor Francoise Cathala and history of prions diseases].

    Science.gov (United States)

    Court, L; Hauw, J-J

    2015-12-01

    Doctor Françoise Cathala Pagesy, MD, MS, born on July 7, 1921 in Paris, passed away peacefully at home on November 5, 2012. Unconventional, passionate and enthusiastic neurologist and virologist, she devoted her life to research on latent and slow viral infections, specializing mainly on unconventional transmissible agents or prions. As a research member of Inserm (French Institute for Medical Research), she soon joined the team of Carlton Gajdusek (the NINCDS - National Institute of Nervous Central System and Stroke - of NIH), who first demonstrated the transmissibility of kuru and Creutzfeldt-Jakob disease to monkeys. When she came back to Paris, where she was followed by one of NIH members, Paul Brown, she joined the Centre de Recherches du Service de Santé des Armées (Army Health Research Center), in Percy-Clamart, where she found the experimental design and the attentive help needed for her research, which appeared heretical to many French virologists, including some authorities. A large number of research programs were set up with numerous collaborations involving CEA (Center for Atomic Energy) and other institutions in Paris and Marseilles on epidemiology, results of tissue inoculation, electrophysiology and neuropathology of human and animal prions diseases, and resistance of the infectious agent. International symposia were set up, where met, in the Val-de-Grâce hospital in Paris, the research community on "slow viral diseases". Stanley Prusiner introduced the concept - then badly accepted and still in evolution - of prion, a protein only infectious agent. Before retiring from Inserm, Françoise Cathala predicted and was involved in some of the huge sanitary crises in France. These were, first, Creutzfeldt-Jakob disease from contaminated growth hormone extracted from cadavers, which led parents to instigate legal procedure - a quite unusual practice in France. The second was Mad cow disease in the United Kingdom then in France, followed by new variant

  15. [Doctor Francoise Cathala and history of prions diseases].

    Science.gov (United States)

    Court, L; Hauw, J-J

    2015-12-01

    Doctor Françoise Cathala Pagesy, MD, MS, born on July 7, 1921 in Paris, passed away peacefully at home on November 5, 2012. Unconventional, passionate and enthusiastic neurologist and virologist, she devoted her life to research on latent and slow viral infections, specializing mainly on unconventional transmissible agents or prions. As a research member of Inserm (French Institute for Medical Research), she soon joined the team of Carlton Gajdusek (the NINCDS - National Institute of Nervous Central System and Stroke - of NIH), who first demonstrated the transmissibility of kuru and Creutzfeldt-Jakob disease to monkeys. When she came back to Paris, where she was followed by one of NIH members, Paul Brown, she joined the Centre de Recherches du Service de Santé des Armées (Army Health Research Center), in Percy-Clamart, where she found the experimental design and the attentive help needed for her research, which appeared heretical to many French virologists, including some authorities. A large number of research programs were set up with numerous collaborations involving CEA (Center for Atomic Energy) and other institutions in Paris and Marseilles on epidemiology, results of tissue inoculation, electrophysiology and neuropathology of human and animal prions diseases, and resistance of the infectious agent. International symposia were set up, where met, in the Val-de-Grâce hospital in Paris, the research community on "slow viral diseases". Stanley Prusiner introduced the concept - then badly accepted and still in evolution - of prion, a protein only infectious agent. Before retiring from Inserm, Françoise Cathala predicted and was involved in some of the huge sanitary crises in France. These were, first, Creutzfeldt-Jakob disease from contaminated growth hormone extracted from cadavers, which led parents to instigate legal procedure - a quite unusual practice in France. The second was Mad cow disease in the United Kingdom then in France, followed by new variant

  16. Prominent pancreatic endocrinopathy and altered control of food intake disrupt energy homeostasis in prion diseases

    Science.gov (United States)

    Bailey, J.D.; Berardinelli, J.G.; Rocke, T.E.; Bessen, R.A.

    2008-01-01

    Prion diseases are fatal neurodegenerative diseases that can induce endocrinopathies. The basis of altered endocrine function in prion diseases is not well understood, and the purpose of this study was to investigate the spatiotemporal relationship between energy homeostasis and prion infection in hamsters inoculated with either the 139H strain of scrapie agent, which induces preclinical weight gain, or the HY strain of transmissible mink encephalopathy (TME), which induces clinical weight loss. Temporal changes in body weight, feed, and water intake were measured as well as both non-fasted and fasted concentrations of serum glucose, insulin, glucagon, ??-ketones, and leptin. In 139H scrapie-infected hamsters, polydipsia, hyperphagia, non-fasted hyperinsulinemia with hyperglycemia, and fasted hyperleptinemia were found at preclinical stages and are consistent with an anabolic syndrome that has similarities to type II diabetes mellitus and/or metabolic syndrome X. In HY TME-infected hamsters, hypodipsia, hypersecretion of glucagon (in both non-fasted and fasted states), increased fasted ??-ketones, fasted hypoglycemia, and suppressed non-fasted leptin concentrations were found while feed intake was normal. These findings suggest a severe catabolic syndrome in HY TME infection mediated by chronic increases in glucagon secretion. In both models, alterations of pancreatic endocrine function were not associated with PrPSc deposition in the pancreas. The results indicate that prominent endocrinopathy underlies alterations in body weight, pancreatic endocrine function, and intake of food. The prion-induced alterations of energy homeostasis in 139H scrapie- or HY TME-infected hamsters could occur within areas of the hypothalamus that control food satiety and/or within autonomic centers that provide neural outflow to the pancreas. ?? 2008 Society for Endocrinology.

  17. Inherited prion disease with 4-octapeptide repeat insertion: disease requires the interaction of multiple genetic risk factors.

    Science.gov (United States)

    Kaski, Diego N; Pennington, Catherine; Beck, Jon; Poulter, Mark; Uphill, James; Bishop, Matthew T; Linehan, Jaqueline M; O'Malley, Catherine; Wadsworth, Jonathan D F; Joiner, Susan; Knight, Richard S G; Ironside, James W; Brandner, Sebastian; Collinge, John; Mead, Simon

    2011-06-01

    Genetic factors are implicated in the aetiology of sporadic late-onset neurodegenerative diseases. Whether these genetic variants are predominantly common or rare, and how multiple genetic factors interact with each other to cause disease is poorly understood. Inherited prion diseases are highly heterogeneous and may be clinically mistaken for sporadic Creutzfeldt-Jakob disease because of a negative family history. Here we report our investigation of patients from the UK with four extra octapeptide repeats, which suggest that the risk of clinical disease is increased by a combination of the mutation and a susceptibility haplotype on the wild-type chromosome. The predominant clinical syndrome is a progressive cortical dementia with pyramidal signs, myoclonus and cerebellar abnormalities that closely resemble sporadic Creutzfeldt-Jakob disease. Autopsy shows perpendicular deposits of prion protein in the molecular layer of the cerebellum. Identity testing, PRNP microsatellite haplotyping and genealogical work confirm no cryptic close family relationships and suggests multiple progenitor disease haplotypes. All patients were homozygous for methionine at polymorphic codon 129. In addition, at a single nucleotide polymorphism upstream of PRNP thought to confer susceptibility to sporadic Creutzfeldt-Jakob disease (rs1029273), all patients were homozygous for the risk allele (combined P=5.9×10(-5)). The haplotype identified may also be a risk factor in other partially penetrant inherited prion diseases although it does not modify age of onset. Blood expression of PRNP in healthy individuals was modestly higher in carriers of the risk haplotype. These findings may provide a precedent for understanding apparently sporadic neurodegenerative diseases caused by rare high-risk mutations. PMID:21616973

  18. Prion Diseases: Update on Mad Cow Disease, Variant Creutzfeldt-Jakob Disease, and the Transmissible Spongiform Encephalopathies.

    Science.gov (United States)

    Janka, Jacqueline; Maldarelli, Frank

    2004-08-01

    Transmissible spongiform encephalopathies (TSEs) are a group of progressive, fatal neurodegenerative disorders that share a common spongiform histopathology. TSEs may be transmitted in a sporadic, familial, iatrogenic, or zoonotic fashion. The putative infectious agent of TSE, the prion, represents a novel paradigm of infectious disease with disease transmission in the absence of nucleic acid. Several small but spectacular epidemics of TSEs in man have prompted widespread public health and food safety concerns. Although TSEs affect a comparatively small number of individuals, prion research has revealed fascinating insights of direct relevance to common illnesses. This paper reviews recent advances that have shed new light on the nature of prions and TSEs. PMID:15265460

  19. Peripheral prion disease pathogenesis is unaltered in the absence of sialoadhesin (Siglec-1/CD169).

    Science.gov (United States)

    Bradford, Barry M; Crocker, Paul R; Mabbott, Neil A

    2014-09-01

    Prions are a unique group of pathogens, which are considered to comprise solely of an abnormally folded isoform of the cellular prion protein. The accumulation and replication of prions within secondary lymphoid organs is important for their efficient spread from the periphery to the brain where they ultimately cause neurodegeneration and death. Mononuclear phagocytes (MNP) play key roles in prion disease pathogenesis. Some MNP appear to facilitate the propagation of prions to and within lymphoid tissues, whereas others may aid their clearance by phagocytosis and by destroying them. Our recent data show that an intact splenic marginal zone is important for the efficient delivery of prions into the B-cell follicles where they subsequently replicate upon follicular dendritic cells before infecting the nervous system. Sialoadhesin is an MNP-restricted cell adhesion molecule that binds sialylated glycoproteins. Sialoadhesin is constitutively expressed upon splenic marginal zone metallophilic and lymph node sub-capsular sinus macrophage populations, where it may function to bind sialylated glycoproteins, pathogens and exosomes in the blood and lymph via recognition of terminal sialic acid residues. As the prion glycoprotein is highly sialylated, we tested the hypothesis that sialoadhesin may influence prion disease pathogenesis. We show that after peripheral exposure, prion pathogenesis was unaltered in sialoadhesin-deficient mice; revealing that lymphoid sequestration of prions is not mediated via sialoadhesin. Hence, although an intact marginal zone is important for the efficient uptake and delivery of prions into the B-cell follicles of the spleen, this is not influenced by sialoadhesin expression by the MNP within it. PMID:24684244

  20. Inherited prion disease with A117V mutation of the prion protein gene: a novel Hungarian family

    OpenAIRE

    Kovacs, G; Ertsey, C; Majtenyi, C; Jelencsik, I; Laszlo, L; Flicker, H; Strain, L.; Szirmai, I; Budka, H.

    2001-01-01

    Three members of a family with inherited prion disease are reported. One additional family member had a progressive neurological disease without details. Two developed symptoms of ataxia, dementia, myoclonus, rigidity, and hemiparesis, and one had a different phenotype with the combination of lower motor neuron deficit, parkinsonism, intellectual decline, and ataxia. In this last patient cell loss of the anterior horn motor neurons and chronic neurogenic muscle atrophy was evid...

  1. Polymorphisms in the prion protein gene and in the doppel gene increase susceptibility for Creutzfeldt-Jakob disease

    NARCIS (Netherlands)

    Croes, EA; Alizadeh, BZ; Bertoli-Avella, AM; Rademaker, T; Vergeer-Drop, J; Dermaut, B; Houwing-Duistermaat, JJ; Wientjens, DPWM; Hofman, A; Van Broeckhoven, C; van Duijn, CM

    2004-01-01

    The prion protein gene (PRNP) plays a central role in the origin of Creutzfeldt - Jakob disease (CJD), but there is growing interest in other polymorphisms that may be involved in CJD. Polymorphisms upstream of PRNP that may modulate the prion protein production as well as polymorphisms in the prion

  2. 朊病毒病的研究进展%The research progress of prion diseases

    Institute of Scientific and Technical Information of China (English)

    卢韦华琳

    2013-01-01

      朊病毒病是一类由朊病毒引起的致死性神经退行性疾病,对人类社会的危害日益明显。本文就朊病毒病的致病机制、检测及治疗的研究进展做一综述。%Prion diseases are fatal neurodegenerative diseases caused by prions,the harm to the human society is increasingly evident.This article do a review on the pathogenic mechanisms、 detection and treatment of prion diseases.

  3. The research progress of prion diseases%朊病毒病的研究进展

    Institute of Scientific and Technical Information of China (English)

    卢韦华琳

    2013-01-01

      朊病毒病是一类由朊病毒引起的致死性神经退行性疾病,对人类社会的危害日益明显。本文就朊病毒病的致病机制、检测及治疗的研究进展做一综述。%Prion diseases are fatal neurodegenerative diseases caused by prions,the harm to the human society is increasingly evident.This article do a review on the pathogenic mechanisms、 detection and treatment of prion diseases.

  4. Morphological and Functional Abnormalities in Mitochondria Associated with Synaptic Degeneration in Prion Disease

    OpenAIRE

    Sisková, Zuzana; Mahad, Don Joseph; Pudney, Carianne; Campbell, Graham; Cadogan, Mark; Asuni, Ayodeji; O'Connor, Vincent; Perry, Victor Hugh

    2010-01-01

    Synaptic and dendritic pathology is a well-documented component of prion disease. In common with other neurodegenerative diseases that contain an element of protein misfolding, little is known about the underlying mechanisms of synaptic degeneration. In particular, in prion disease the relationship between synaptic malfunction, degeneration, and mitochondria has been neglected. We investigated a wide range of mitochondrial parameters, including changes in mitochondrial density, inner membrane...

  5. MicroRNA abundance is altered in synaptoneurosomes during prion disease.

    Science.gov (United States)

    Boese, Amrit S; Saba, Reuben; Campbell, Kristyn; Majer, Anna; Medina, Sarah; Burton, Lynn; Booth, Timothy F; Chong, Patrick; Westmacott, Garrett; Dutta, Sucharita M; Saba, Julian A; Booth, Stephanie A

    2016-03-01

    Discrepancy in synaptic structural plasticity is one of the earliest manifestations of the neurodegenerative state. In prion diseases, a reduction in synapses and dendritic spine densities is observed during preclinical disease in neurons of the cortex and hippocampus. The underlying molecular mechanisms of these alterations have not been identified but microRNAs (miRNAs), many of which are enriched at the synapse, likely regulate local protein synthesis in rapid response to stressors such as replicating prions. MiRNAs are therefore candidate regulators of these early neurodegenerative changes and may provide clues as to the molecular pathways involved. We therefore determined changes in mature miRNA abundance within synaptoneurosomes isolated from prion-infected, as compared to mock-infected animals, at asymptomatic and symptomatic stages of disease. During preclinical disease, miRNAs that are enriched in neurons including miR-124a-3p, miR-136-5p and miR-376a-3p were elevated. At later stages of disease we found increases in miRNAs that have previously been identified as deregulated in brain tissues of prion infected mice, as well as in Alzheimer's disease (AD) models. These include miR-146a-5p, miR-142-3p, miR-143-3p, miR-145a-5p, miR-451a, miR-let-7b, miR-320 and miR-150-5p. A number of miRNAs also decreased in abundance during clinical disease. These included almost all members of the related miR-200 family (miR-200a-3p, miR-200b-3p, miR-200c-3p, miR-141-3p, and miR-429-3p) and the 182 cluster (miR-182-5p and miR-183-5p). PMID:26658803

  6. Crystallographic Studies of Prion Protein (PrP) Segments Suggest How Structural Changes Encoded by Polymorphism at Residue 129 Modulate Susceptibility to Human Prion Disease

    Energy Technology Data Exchange (ETDEWEB)

    Apostol, Marcin I.; Sawaya, Michael R.; Cascio, Duilio; Eisenberg, David (UCLA)

    2010-09-23

    A single nucleotide polymorphism (SNP) in codon 129 of the human prion gene, leading to a change from methionine to valine at residue 129 of prion protein (PrP), has been shown to be a determinant in the susceptibility to prion disease. However, the molecular basis of this effect remains unexplained. In the current study, we determined crystal structures of prion segments having either Met or Val at residue 129. These 6-residue segments of PrP centered on residue 129 are 'steric zippers,' pairs of interacting {beta}-sheets. Both structures of these 'homozygous steric zippers' reveal direct intermolecular interactions between Met or Val in one sheet and the identical residue in the mating sheet. These two structures, plus a structure-based model of the heterozygous Met-Val steric zipper, suggest an explanation for the previously observed effects of this locus on prion disease susceptibility and progression.

  7. Metabolism of minor isoforms of prion proteins: Cytosolic prion protein and transmembrane prion protein

    OpenAIRE

    Song, Zhiqi; Zhao, Deming; Yang, Lifeng

    2013-01-01

    Transmissible spongiform encephalopathy or prion disease is triggered by the conversion from cellular prion protein to pathogenic prion protein. Growing evidence has concentrated on prion protein configuration changes and their correlation with prion disease transmissibility and pathogenicity. In vivo and in vitro studies have shown that several cytosolic forms of prion protein with specific topological structure can destroy intracellular stability and contribute to prion protein pathogenicit...

  8. The Gut-Associated Lymphoid Tissues in the Small Intestine, Not the Large Intestine, Play a Major Role in Oral Prion Disease Pathogenesis

    OpenAIRE

    David DONALDSON; Else, Kathryn J.; Mabbott, Neil

    2015-01-01

    ABSTRACT Prion diseases are infectious neurodegenerative disorders characterized by accumulations of abnormally folded cellular prion protein in affected tissues. Many natural prion diseases are acquired orally, and following exposure, the early replication of some prion isolates upon follicular dendritic cells (FDC) within gut-associated lymphoid tissues (GALT) is important for the efficient spread of disease to the brain (neuroinvasion). Prion detection within large intestinal GALT biopsy s...

  9. Towards authentic transgenic mouse models of heritable PrP prion diseases.

    Science.gov (United States)

    Watts, Joel C; Giles, Kurt; Bourkas, Matthew E C; Patel, Smita; Oehler, Abby; Gavidia, Marta; Bhardwaj, Sumita; Lee, Joanne; Prusiner, Stanley B

    2016-10-01

    Attempts to model inherited human prion disorders such as familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) disease, and fatal familial insomnia (FFI) using genetically modified mice have produced disappointing results. We recently demonstrated that transgenic (Tg) mice expressing wild-type bank vole prion protein (BVPrP) containing isoleucine at polymorphic codon 109 develop a spontaneous neurodegenerative disorder that exhibits many of the hallmarks of prion disease. To determine if mutations causing inherited human prion disease alter this phenotype, we generated Tg mice expressing BVPrP containing the D178N mutation, which causes FFI; the E200K mutation, which causes familial CJD; or an anchorless PrP mutation similar to mutations that cause GSS. Modest expression levels of mutant BVPrP resulted in highly penetrant spontaneous disease in Tg mice, with mean ages of disease onset ranging from ~120 to ~560 days. The brains of spontaneously ill mice exhibited prominent features of prion disease-specific neuropathology that were unique to each mutation and distinct from Tg mice expressing wild-type BVPrP. An ~8-kDa proteinase K-resistant PrP fragment was found in the brains of spontaneously ill Tg mice expressing either wild-type or mutant BVPrP. The spontaneously formed mutant BVPrP prions were transmissible to Tg mice expressing wild-type or mutant BVPrP as well as to Tg mice expressing mouse PrP. Thus, Tg mice expressing mutant BVPrP exhibit many of the hallmarks of heritable prion disorders in humans including spontaneous disease, protease-resistant PrP, and prion infectivity. PMID:27350609

  10. Human tonsil-derived follicular dendritic-like cells are refractory to human prion infection in vitro and traffic disease-associated prion protein to lysosomes.

    Science.gov (United States)

    Krejciova, Zuzana; De Sousa, Paul; Manson, Jean; Ironside, James W; Head, Mark W

    2014-01-01

    The molecular mechanisms involved in human cellular susceptibility to prion infection remain poorly defined. This is due, in part, to the absence of any well characterized and relevant cultured human cells susceptible to infection with human prions, such as those involved in Creutzfeldt-Jakob disease. In variant Creutzfeldt-Jakob disease, prion replication is thought to occur first in the lymphoreticular system and then spread into the brain. We have, therefore, examined the susceptibility of a human tonsil-derived follicular dendritic cell-like cell line (HK) to prion infection. HK cells were found to display a readily detectable, time-dependent increase in cell-associated abnormal prion protein (PrP(TSE)) when exposed to medium spiked with Creutzfeldt-Jakob disease brain homogenate, resulting in a coarse granular perinuclear PrP(TSE) staining pattern. Despite their high level of cellular prion protein expression, HK cells failed to support infection, as judged by longer term maintenance of PrP(TSE) accumulation. Colocalization studies revealed that exposure of HK cells to brain homogenate resulted in increased numbers of detectable lysosomes and that these structures immunostained intensely for PrP(TSE) after exposure to Creutzfeldt-Jakob disease brain homogenate. Our data suggest that human follicular dendritic-like cells and perhaps other human cell types are able to avoid prion infection by efficient lysosomal degradation of PrP(TSE). PMID:24183781

  11. "Protein-only" or "virino" in prion diseases?

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    60-year prion and scrapie research has led to a dilemma in understanding the unknown aetiology of the infectious neurodegenerative disorders with intriguing features. Current progress and dilemma in prion research are briefly but critically reviewed. Instead of providing a comprehensive coverage of the research history, attentions in this view are drawn toward both the major breakthrough in the advancement of protein-only hypothesis, and the puzzle why this hypothesis has not been fully accepted. In order to resolve the prion enigma in neuroscience, it is suggested that both technical and concept barriers remain to be crossed. Since prion research is a multi-interdisciplinary subject, this view is intended to both facilitate a better understanding of prion phenomenon by more scientists in natural science, and invite scientists outside the fields of molecular genetics and protein science for collaboration.

  12. Utilizing NMR and EPR spectroscopy to probe the role of copper in prion diseases

    KAUST Repository

    Emwas, Abdul-Hamid M.

    2013-02-24

    Copper is an essential nutrient for the normal development of the brain and nervous system, although the hallmark of several neurological diseases is a change in copper concentrations in the brain and central nervous system. Prion protein (PrP) is a copper-binding, cell-surface glycoprotein that exists in two alternatively folded conformations: a normal isoform (PrPC) and a disease-associated isoform (PrPSc). Prion diseases are a group of lethal neurodegenerative disorders that develop as a result of conformational conversion of PrPC into PrPSc. The pathogenic mechanism that triggers this conformational transformation with the subsequent development of prion diseases remains unclear. It has, however, been shown repeatedly that copper plays a significant functional role in the conformational conversion of prion proteins. In this review, we focus on current research that seeks to clarify the conformational changes associated with prion diseases and the role of copper in this mechanism, with emphasis on the latest applications of NMR and EPR spectroscopy to probe the interactions of copper with prion proteins. Copyright © 2013 John Wiley & Sons, Ltd.

  13. Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases.

    Science.gov (United States)

    Kabir, M Enamul; Safar, Jiri G

    2014-01-01

    There is a growing body of evidence indicating that number of human neurodegenerative diseases, including Alzheimer disease, Parkinson disease, fronto-temporal dementias, and amyotrophic lateral sclerosis, propagate in the brain via prion-like intercellular induction of protein misfolding. Prions cause lethal neurodegenerative diseases in humans, the most prevalent being sporadic Creutzfeldt-Jakob disease (sCJD); they self-replicate and spread by converting the cellular form of prion protein (PrP(C)) to a misfolded pathogenic conformer (PrP(Sc)). The extensive phenotypic heterogeneity of human prion diseases is determined by polymorphisms in the prion protein gene, and by prion strain-specific conformation of PrP(Sc). Remarkably, even though informative nucleic acid is absent, prions may undergo rapid adaptation and evolution in cloned cells and upon crossing the species barrier. In the course of our investigation of this process, we isolated distinct populations of PrP(Sc) particles that frequently co-exist in sCJD. The human prion particles replicate independently and undergo competitive selection of those with lower initial conformational stability. Exposed to mutant substrate, the winning PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to the lowest stability. Thus, the evolution and adaptation of human prions is enabled by a dynamic collection of distinct populations of particles, whose evolution is governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers. This fundamental biological mechanism may explain the drug resistance that some prions gained after exposure to compounds targeting PrP(Sc). Whether the phenotypic heterogeneity of other neurodegenerative diseases caused by protein misfolding is determined by the spectrum of misfolded conformers (strains) remains to be established. However, the prospect that these conformers may evolve and

  14. Migration of dendritic cells into the brain in a mouse model of prion disease.

    Science.gov (United States)

    Rosicarelli, Barbara; Serafini, Barbara; Sbriccoli, Marco; Lu, Mei; Cardone, Franco; Pocchiari, Maurizio; Aloisi, Francesca

    2005-08-01

    The immune system plays a key role in the dissemination of prion infections from the periphery to the central nervous system (CNS). While follicular dendritic cells are critical for prion replication in lymphoid tissue and subsequent neuroinvasion, myeloid dendritic cells (DCs) have been implicated in both the clearance and propagation of pathological prion protein. Since nothing is known on the ability of DCs to migrate to the CNS during prion diseases, we investigated the immunohistochemical localization of CD205(+) DCs in the brain of C57BL/6 mice intraperitoneally infected with the mouse-adapted KFu strain of Gerstmann-Sträussler-Scheinker syndrome, a human genetic prion disorder. In normal brain, CD205(+) cells were present in the meninges and choroid plexus, whereas in the majority of mice sacrificed between 120 and 300 days post infection, CD205(+) DCs were also detected in the cerebral cortex, subcortical white matter, thalamus and medulla oblongata. These findings demonstrate that DCs can enter the CNS of prion-infected mice, suggesting a possible role for these cells in the pathogenesis of prion disorders. PMID:15949848

  15. Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents.

    Science.gov (United States)

    Karapetyan, Yervand Eduard; Sferrazza, Gian Franco; Zhou, Minghai; Ottenberg, Gregory; Spicer, Timothy; Chase, Peter; Fallahi, Mohammad; Hodder, Peter; Weissmann, Charles; Lasmézas, Corinne Ida

    2013-04-23

    Prion diseases such as Creutzfeldt-Jakob disease (CJD) are incurable and rapidly fatal neurodegenerative diseases. Because prion protein (PrP) is necessary for prion replication but dispensable for the host, we developed the PrP-FRET-enabled high throughput assay (PrP-FEHTA) to screen for compounds that decrease PrP expression. We screened a collection of drugs approved for human use and identified astemizole and tacrolimus, which reduced cell-surface PrP and inhibited prion replication in neuroblastoma cells. Tacrolimus reduced total cellular PrP levels by a nontranscriptional mechanism. Astemizole stimulated autophagy, a hitherto unreported mode of action for this pharmacophore. Astemizole, but not tacrolimus, prolonged the survival time of prion-infected mice. Astemizole is used in humans to treat seasonal allergic rhinitis in a chronic setting. Given the absence of any treatment option for CJD patients and the favorable drug characteristics of astemizole, including its ability to cross the blood-brain barrier, it may be considered as therapy for CJD patients and for prophylactic use in familial prion diseases. Importantly, our results validate PrP-FEHTA as a method to identify antiprion compounds and, more generally, FEHTA as a unique drug discovery platform. PMID:23576755

  16. Prion protein NMR structure and species barrier for prion diseases

    OpenAIRE

    Billeter, Martin; Riek, Roland; Wider, Gerhard; Hornemann, Simone; Glockshuber, Rudi; Wüthrich, Kurt

    1997-01-01

    The structural basis of species specificity of transmissible spongiform encephalopathies, such as bovine spongiform encephalopathy or “mad cow disease” and Creutzfeldt–Jakob disease in humans, has been investigated using the refined NMR structure of the C-terminal domain of the mouse prion protein with residues 121–231. A database search for mammalian prion proteins yielded 23 different sequences for the fragment 124–226, which display a high degree of sequence identity and show relevant amin...

  17. The sequential development of abnormal prion protein accumulation in mice with Creutzfeldt-Jakob disease.

    OpenAIRE

    Muramoto, T; Kitamoto, T.; Tateishi, J.; Goto, I.

    1992-01-01

    The distribution and sequential development of prion protein (PrP) accumulation in the central nervous system (CNS) and non-neuronal organs of mice infected with Creutzfeldt-Jakob disease (CJD) were investigated immunohistochemically using a new pretreatment method that greatly enhanced the immunoreactivity of PrP. Prion protein accumulation in the CNS was first detected at 30 days after inoculation and then developed near the inoculation site or periventricular area, and later spread to the ...

  18. Sod1 deficiency reduces incubation time in mouse models of prion disease.

    Directory of Open Access Journals (Sweden)

    Shaheen Akhtar

    Full Text Available Prion infections, causing neurodegenerative conditions such as Creutzfeldt-Jakob disease and kuru in humans, scrapie in sheep and BSE in cattle are characterised by prolonged and variable incubation periods that are faithfully reproduced in mouse models. Incubation time is partly determined by genetic factors including polymorphisms in the prion protein gene. Quantitative trait loci studies in mice and human genome-wide association studies have confirmed that multiple genes are involved. Candidate gene approaches have also been used and identified App, Il1-r1 and Sod1 as affecting incubation times. In this study we looked for an association between App, Il1-r1 and Sod1 representative SNPs and prion disease incubation time in the Northport heterogeneous stock of mice inoculated with the Chandler/RML prion strain. No association was seen with App, however, significant associations were seen with Il1-r1 (P = 0.02 and Sod1 (P<0.0001 suggesting that polymorphisms at these loci contribute to the natural variation observed in incubation time. Furthermore, following challenge with Chandler/RML, ME7 and MRC2 prion strains, Sod1 deficient mice showed highly significant reductions in incubation time of 20, 13 and 24%, respectively. No differences were detected in Sod1 expression or activity. Our data confirm the protective role of endogenous Sod1 in prion disease.

  19. Prions in Yeast

    OpenAIRE

    Liebman, Susan W; Chernoff, Yury O.

    2012-01-01

    The concept of a prion as an infectious self-propagating protein isoform was initially proposed to explain certain mammalian diseases. It is now clear that yeast also has heritable elements transmitted via protein. Indeed, the “protein only” model of prion transmission was first proven using a yeast prion. Typically, known prions are ordered cross-β aggregates (amyloids). Recently, there has been an explosion in the number of recognized prions in yeast. Yeast continues to lead the way in unde...

  20. Meat and bone meal and mineral feed additives may increase the risk of oral prion disease transmission

    Science.gov (United States)

    Johnson, Christopher J.; McKenzie, Debbie; Pedersen, Joel A.; Aiken, Judd M.

    2011-01-01

    Ingestion of prion-contaminated materials is postulated to be a primary route of prion disease transmission. Binding of prions to soil (micro)particles dramatically enhances peroral disease transmission relative to unbound prions, and it was hypothesized that micrometer-sized particles present in other consumed materials may affect prion disease transmission via the oral route of exposure. Small, insoluble particles are present in many substances, including soil, human foods, pharmaceuticals, and animal feeds. It is known that meat and bone meal (MBM), a feed additive believed responsible for the spread of bovine spongiform encephalopathy (BSE), contains particles smaller than 20 μm and that the pathogenic prion protein binds to MBM. The potentiation of disease transmission via the oral route by exposure to MBM or three micrometer-sized mineral feed additives was determined. Data showed that when the disease agent was bound to any of the tested materials, the penetrance of disease was increased compared to unbound prions. Our data suggest that in feed or other prion-contaminated substances consumed by animals or, potentially, humans, the addition of MBM or the presence of microparticles could heighten risks of prion disease acquisition.

  1. Helicobacter pylori upregulates prion protein expression in gastric mucosa: A possible link to prion disease

    Institute of Scientific and Technical Information of China (English)

    Peter C Konturek; Karolina Bazela; Vitaliy Kukharskyy; Michael Bauer; Eckhart G Hahn; Detlef Schuppan

    2005-01-01

    AIM: Pathological prion protein (PrPSC) is responsible for the development of transmissible spongiform encephalopathies (TSE). While PrPc enters the organism via the oral route, less data is available to know about its uptake and the role of gastrointestinal inflammation on the expression of prion precursor PrPc, which is constitutively expressed in the gastric mucosa.METHODS: We studied PrPc expression in the gastric mucosa of 10 Helicobacter pylori-positive patients before and after successful H pylori eradication compared to non-infected controls using RT-PCR and Western blotting.The effect of central mediators of gastric inflammation,i.e., gastrin, prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) on PrPc expression was analyzed in gastric cell lines.RESULTS: PrPc expression was increased in H pyloriinfection compared with non-infected controls and decreased to normal after successful eradication. Gastrin,PGE2, and IL-1β dose-dependently upregulated PrPc in gastric cells, while TNF-α had no effect.CONCLUSION: H pylori infection leads to the upregulation of gastric PrPc expression. This can be linked to H pylori induced hypergastrinemia and increased mucosal PGE2 and IL-1β synthesis.H pylori creates a milieu for enhanced propagation of prions in the gastrointestinal tract.

  2. Phosphatidylinositol-glycan-phospholipase D is involved in neurodegeneration in prion disease.

    Directory of Open Access Journals (Sweden)

    Jae-Kwang Jin

    Full Text Available PrPSc is formed from a normal glycosylphosphatidylinositol (GPI-anchored prion protein (PrPC by a posttranslational modification. Most GPI-anchored proteins have been shown to be cleaved by GPI phospholipases. Recently, GPI-phospholipase D (GPI-PLD was shown to be a strictly specific enzyme for GPI anchors. To investigate the involvement of GPI-PLD in the processes of neurodegeneration in prion diseases, we examined the mRNA and protein expression levels of GPI-PLD in the brains of a prion animal model (scrapie, and in both the brains and cerebrospinal fluids (CSF of sporadic and familial Creutzfeldt-Jakob disease (CJD patients. We found that compared with controls, the expression of GPI-PLD was dramatically down-regulated in the brains of scrapie-infected mice, especially in the caveolin-enriched membrane fractions. Interestingly, the observed decrease in GPI-PLD expression levels began at the same time that PrPSc began to accumulate in the infected brains and this decrease was also observed in both the brain and CSF of CJD patients; however, no differences in expression were observed in either the brains or CSF specimens from Alzheimer's disease patients. Taken together, these results suggest that the down-regulation of GPI-PLD protein may be involved in prion propagation in the brains of prion diseases.

  3. Structure-Based Drug Discovery for Prion Disease Using a Novel Binding Simulation

    Directory of Open Access Journals (Sweden)

    Daisuke Ishibashi

    2016-07-01

    Full Text Available The accumulation of abnormal prion protein (PrPSc converted from the normal cellular isoform of PrP (PrPC is assumed to induce pathogenesis in prion diseases. Therefore, drug discovery studies for these diseases have focused on the protein conversion process. We used a structure-based drug discovery algorithm (termed Nagasaki University Docking Engine: NUDE that ran on an intensive supercomputer with a graphic-processing unit to identify several compounds with anti-prion effects. Among the candidates showing a high-binding score, the compounds exhibited direct interaction with recombinant PrP in vitro, and drastically reduced PrPSc and protein-aggresomes in the prion-infected cells. The fragment molecular orbital calculation showed that the van der Waals interaction played a key role in PrPC binding as the intermolecular interaction mode. Furthermore, PrPSc accumulation and microgliosis were significantly reduced in the brains of treated mice, suggesting that the drug candidates provided protection from prion disease, although further in vivo tests are needed to confirm these findings. This NUDE-based structure-based drug discovery for normal protein structures is likely useful for the development of drugs to treat other conformational disorders, such as Alzheimer's disease.

  4. A prion primer

    OpenAIRE

    Cashman, N R

    1997-01-01

    By biological and medical criteria, prions are infectious agents; however, many of their properties differ profoundly from those of conventional microbes. Prions are "encoded" by alterations in protein conformation rather than in nucleic acid or amino acid sequence. New epidemic prion diseases (bovine spongiform encephalopathy and new variant Creutzfeldt-Jakob disease) have recently emerged under the active surveillance of the modern world. The risk of contracting prion disease from blood pro...

  5. Correlation between prion protein gene codon 129 polymorphism and late-onset Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Hairong Qian; Luning Wang; Xiaokun Qi; Jianwei Liu; Jing Liu; Ling Ye; Hengge Xie; Wei Wang; Feng Qiu

    2009-01-01

    BACKGROUND:Studies addressing the correlation between prion protein gene codon 129 polymorphism,Alzheimer's disease,and cognitive disorders have mainly focused on Caucasians.However,prion protein gene codon 129 polymorphism is thought to also affect the Chinese Han and Wei populations.OBJECTIVE:To analyze the differences of prion protein gene codon 129 distribution among the elderly Chinese Han,East Asian,and Caucasian populations,and to study the correlation between prion protein gene codon 129 distribution and late-onset Alzheimer's disease.DESIGN,TIME AND SETTING:A gene polymorphism analysis was performed in the Institute of Geriatrics,General Hospital of Chinese PLA between January 2006 and January 2007.PARTICIPANTS:A total of 152 elderly Chinese Han people were selected from the Beijing Troop Cadre's Sanitarium.Among them,60 patients with late-onset Alzheimer's disease,with a mean age of (82±7) years (range 67-94 years) and disease course of (5.9±4.4) years,comprising 44 males with a mean age of (83±7) years and 16 females with a mean age of (78±7) years,were selected for the case group.An additional 92 healthy elderly subjects,with a mean of (76±9) years (range 60-94 years),comprising 76 males with a mean age of (77±9) years and 16 females with a mean age of (70±8) years,were selected for the control group.There were no significant differences in age and gender between the two groups (P>0.05).METHODS:DNA was extracted from peripheral blood leukocytes using routine phenol/chloroform methodology.Prion protein gene codon 129 polymorphism and ApoE polymorphism were measured using PCR-restriction fragment length polymorphism.The ApoEε allele was considered the standard for analyzing correlations between prion protein gene codon 129 polymorphism and late-onset Alzheimer's disease.MAIN OUTCOME MEASURES:Prion protein gene codon 129 distribution;correlation between genotypic frequency and allele frequency of prion protein gene codon 129 with Alzheimer

  6. Potential contribution of exosomes to the prion-like propagation of lesions in Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Valerie eVingtdeux

    2012-07-01

    Full Text Available Since the discovery of prion diseases, the concept that a transmissible pathogen could be a protein has emerged. As such, this transmissible protein agent can transfer its pathological mis-folded shape to the same but normally folded protein thus leading to the propagation of a disease. This idea is now extrapolate to several neurological diseases associated with protein mis-folding and aggregation, such as Alzheimer’s disease. Alzheimer’s disease (AD is a slowly developing dementing disease characterized by the coexistence of two types of lesions: the parenchymal amyloid deposits and the intraneuronal neurofibrillary tangles (NFT. Amyloid deposits are composed of amyloid-beta peptides that derive from sequential cleavages of its precursor named amyloid protein precursor. Neurofibrillary tangle is characterized by intraneuronal aggregation of abnormally modified microtubule-associated Tau proteins. A synergistic relationship between the two lesions may trigger the progression of the disease. Thus, starting in the medial temporal lobe and slowly progressing through temporal, frontal, parietal and occipital cortex, the progression of NFT is well correlated with clinical expression of the disease. However, little is known about the mechanism driving the spatiotemporal propagation of these lesions ultimately leading to the disease. A growing number of studies suggest a prion-like diffusion of amyloid deposits and NFT. In the present chapter, we will develop the current hypotheses regarding the molecular and cellular mechanisms driving the development and spreading of Alzheimer disease lesions from the window of multivesicular bodies and exosomes.

  7. The Prion-Like Properties of Amyloid-β Assemblies: Implications for Alzheimer's Disease.

    Science.gov (United States)

    Walker, Lary C; Schelle, Juliane; Jucker, Mathias

    2016-01-01

    Since the discovery that prion diseases can be transmitted to experimental animals by inoculation with afflicted brain matter, researchers have speculated that the brains of patients suffering from other neurodegenerative diseases might also harbor causative agents with transmissible properties. Foremost among these disorders is Alzheimer's disease (AD), the most common cause of dementia in the elderly. A growing body of research supports the concept that the pathogenesis of AD is initiated and sustained by the endogenous, seeded misfolding and aggregation of the protein fragment amyloid-β (Aβ). At the molecular level, this mechanism of nucleated protein self-assembly is virtually identical to that of prions consisting of the prion protein (PrP). The formation, propagation, and spread of Aβ seeds within the brain can thus be considered a fundamental feature of AD pathogenesis. PMID:27270558

  8. The Good, the Bad, and the Ugly of Dendritic Cells during Prion Disease

    Directory of Open Access Journals (Sweden)

    Neil Andrew Mabbott

    2015-01-01

    Full Text Available Prions are a unique group of proteinaceous pathogens which cause neurodegenerative disease and can be transmitted by a variety of exposure routes. After peripheral exposure, the accumulation and replication of prions within secondary lymphoid organs are obligatory for their efficient spread from the periphery to the brain where they ultimately cause neurodegeneration and death. Mononuclear phagocytes (MNP are a heterogeneous population of dendritic cells (DC and macrophages. These cells are abundant throughout the body and display a diverse range of roles based on their anatomical locations. For example, some MNP are strategically situated to provide a first line of defence against pathogens by phagocytosing and destroying them. Conventional DC are potent antigen presenting cells and migrate via the lymphatics to the draining lymphoid tissue where they present the antigens to lymphocytes. The diverse roles of MNP are also reflected in various ways in which they interact with prions and in doing so impact on disease pathogenesis. Indeed, some studies suggest that prions exploit conventional DC to infect the host. Here we review our current understanding of the influence of MNP in the pathogenesis of the acquired prion diseases with particular emphasis on the role of conventional DC.

  9. MRI and MRS alterations in the preclinical phase of murine prion disease: association with neuropathological and behavioural changes.

    Science.gov (United States)

    Broom, Kerry A; Anthony, Daniel C; Lowe, John P; Griffin, Julian L; Scott, Helen; Blamire, Andrew M; Styles, Peter; Perry, V Hugh; Sibson, Nicola R

    2007-06-01

    Prion diseases are fatal chronic neurodegenerative diseases. Previous qualitative magnetic resonance imaging (MRI) and spectroscopy (MRS) studies report conflicting results in the symptomatic stages of the disease, but little work has been carried out during the earlier stages of the disease. Here we have used the murine ME7 model of prion disease to quantitatively investigate MRI and MRS changes during the period prior to the onset of overt clinical signs (20+ weeks) and have correlated these with pathological and behavioural abnormalities. Using in vivo MRI, at the later stages of the preclinical period (18 weeks) the diffusion of tissue water was significantly reduced, coinciding with significant microglial activation and behavioural hyperactivity. Using in vivo MRS, we found early (12 weeks) decreases in the ratio of N-acetyl aspartate to both choline (NAA/Cho) and creatine (NAA/Cr) in the thalamus and hippocampus, which were associated with early behavioural deficits. Ex vivo MRS of brain extracts confirmed and extended these findings, showing early (8-12 weeks) decreases in both the neuronal metabolites NAA and glutamate, and the metabolic metabolites lactate and glucose. Increases in the glial metabolite myo-inositol were observed at later stages when microglial and astrocyte activation is substantial. These changes in MRI and MRS signals, which precede overt clinical signs of disease, could provide insights into the pathogenesis of this disease and may enable early detection of pathology. PMID:17490889

  10. Trafficking and degradation pathways in pathogenic conversion of prions and prion-like proteins in neurodegenerative diseases.

    Science.gov (United States)

    Victoria, Guiliana Soraya; Zurzolo, Chiara

    2015-09-01

    Several neurodegenerative diseases such as transmissible spongiform encephalopathies, Alzheimer's and Parkinson's diseases are caused by the conversion of cellular proteins to a pathogenic conformer. Despite differences in the primary structure and subcellular localization of these proteins, which include the prion protein, α-synuclein and amyloid precursor protein (APP), striking similarity has been observed in their ability to seed and convert naïve protein molecules as well as transfer between cells. This review aims to cover what is known about the intracellular trafficking of these proteins as well as their degradation mechanisms and highlight similarities in their movement through the endocytic pathway that could contribute to the pathogenic conversion and seeding of these proteins which underlies the basis of these diseases.

  11. A distinct proteinase K resistant prion protein fragment in goats with no signs of disease in a classical scrapie outbreak

    NARCIS (Netherlands)

    Bouzalas, I.; Lörtscher, F.; Dovas, C.; Oevermann, A.; Langeveld, J.P.M.; Papanastassopoulou, M.; Papadopoulos, O.; Zurbriggen, A.; Seuberlich, T.

    2011-01-01

    Considerable efforts have been directed toward the identification of small-ruminant prion diseases, i.e., classical and atypical scrapie as well as bovine spongiform encephalopathy (BSE). Here we report the in-depth molecular analysis of the proteinase K-resistant prion protein core fragment (PrPres

  12. Primary transmission of chronic wasting disease versus scrapie prions from small ruminants to transgenic mice expressing ovine and cervid prion protein

    Science.gov (United States)

    Identifying transmissible spongiform encephalopathy (TSE) reservoirs that could lead to disease re-emergence is imperative to U.S. scrapie eradication efforts. Transgenic mice expressing the cervid (TgElk) or ovine (Tg338) prion protein have aided characterization of chronic wasting disease (CWD) an...

  13. Antioxidant and Metal Chelation-Based Therapies in the Treatment of Prion Disease.

    Science.gov (United States)

    Brazier, Marcus W; Wedd, Anthony G; Collins, Steven J

    2014-04-21

    Many neurodegenerative disorders involve the accumulation of multimeric assemblies and amyloid derived from misfolded conformers of constitutively expressed proteins. In addition, the brains of patients and experimental animals afflicted with prion disease display evidence of heightened oxidative stress and damage, as well as disturbances to transition metal homeostasis. Utilising a variety of disease model paradigms, many laboratories have demonstrated that copper can act as a cofactor in the antioxidant activity displayed by the prion protein while manganese has been implicated in the generation and stabilisation of disease-associated conformers. This and other evidence has led several groups to test dietary and chelation therapy-based regimens to manipulate brain metal concentrations in attempts to influence the progression of prion disease in experimental mice. Results have been inconsistent. This review examines published data on transition metal dyshomeostasis, free radical generation and subsequent oxidative damage in the pathogenesis of prion disease. It also comments on the efficacy of trialed therapeutics chosen to combat such deleterious changes.

  14. Antioxidant and Metal Chelation-Based Therapies in the Treatment of Prion Disease

    Directory of Open Access Journals (Sweden)

    Marcus W. Brazier

    2014-04-01

    Full Text Available Many neurodegenerative disorders involve the accumulation of multimeric assemblies and amyloid derived from misfolded conformers of constitutively expressed proteins. In addition, the brains of patients and experimental animals afflicted with prion disease display evidence of heightened oxidative stress and damage, as well as disturbances to transition metal homeostasis. Utilising a variety of disease model paradigms, many laboratories have demonstrated that copper can act as a cofactor in the antioxidant activity displayed by the prion protein while manganese has been implicated in the generation and stabilisation of disease-associated conformers. This and other evidence has led several groups to test dietary and chelation therapy-based regimens to manipulate brain metal concentrations in attempts to influence the progression of prion disease in experimental mice. Results have been inconsistent. This review examines published data on transition metal dyshomeostasis, free radical generation and subsequent oxidative damage in the pathogenesis of prion disease. It also comments on the efficacy of trialed therapeutics chosen to combat such deleterious changes.

  15. MicroRNA and prion disease%MicroRNA与朊病毒疾病

    Institute of Scientific and Technical Information of China (English)

    刘志培; 李忠义; 孟轲音; 杜鹏; 徐静; 万家余; 韩烨

    2013-01-01

    microRNA regulates the expression of cellular protein at post-transcriptional levels, and plays a major role in regulating the development, differentiation and functions of nervous system. Growing evidence indicates that miRNA is involved in the pathogensis of prion disease. Prion disease is a kind of neurodegenerative disease, which has some morphological characteristics, such as ataxia and dementia. In order to explain the pathogenesis, it is also very important to identify these changes in gene expression levels. Therefore, investigation of the roles of miRNA in the pathogenesis of prion disease is very helpful in exploring the mechanisms of prion disease. In this paper, miRNA and neurodegenerative diseases - prion disease research progress are reviewed.%microRNA通过转录后水平调控细胞的蛋白质表达,在神经系统的发育、分化及功能行使中发挥着重要作用.越来越多的证据表明,miRNA与朊病毒疾病的发生有关.朊病毒疾病是一种以共济失调、痴呆为主要特征的神经退行性疾病.为了解释朊病毒疾病的发病机制,在基因表达水平鉴定疾病相关的改变是很重要的.因此,对miRNA在朊病毒疾病中作用的研究不仅有利于疾病发病机制的诠释,也有利于miRNA调控机制的探讨.就miRNA与神经退行性疾病——朊病毒疾病发生的相关研究进展作一综述.

  16. Prions in Variably Protease-Sensitive Prionopathy: An Update

    OpenAIRE

    Laura Pirisinu; Jan Langeveld; Jue Yuan; Xiangzhu Xiao; Wen-Quan Zou; Pierluigi Gambetti

    2013-01-01

    Human prion diseases, including sporadic, familial, and acquired forms such as Creutzfeldt-Jakob disease (CJD), are caused by prions in which an abnormal prion protein (PrPSc) derived from its normal cellular isoform (PrPC) is the only known component. The recently-identified variably protease-sensitive prionopathy (VPSPr) is characterized not only by an atypical clinical phenotype and neuropathology but also by the deposition in the brain of a peculiar PrPSc. Like other forms of human prion ...

  17. Rapid and Highly Sensitive Detection of Variant Creutzfeldt-Jakob Disease Abnormal Prion Protein on Steel Surfaces by Protein Misfolding Cyclic Amplification: Application to Prion Decontamination Studies.

    Science.gov (United States)

    Belondrade, Maxime; Nicot, Simon; Béringue, Vincent; Coste, Joliette; Lehmann, Sylvain; Bougard, Daisy

    2016-01-01

    The prevalence of variant Creutzfeldt-Jakob disease (vCJD) in the population remains uncertain, although it has been estimated that 1 in 2000 people in the United Kingdom are positive for abnormal prion protein (PrPTSE) by a recent survey of archived appendix tissues. The prominent lymphotropism of vCJD prions raises the possibility that some surgical procedures may be at risk of iatrogenic vCJD transmission in healthcare facilities. It is therefore vital that decontamination procedures applied to medical devices before their reprocessing are thoroughly validated. A current limitation is the lack of a rapid model permissive to human prions. Here, we developed a prion detection assay based on protein misfolding cyclic amplification (PMCA) technology combined with stainless-steel wire surfaces as carriers of prions (Surf-PMCA). This assay allowed the specific detection of minute quantities (10-8 brain dilution) of either human vCJD or ovine scrapie PrPTSE adsorbed onto a single steel wire, within a two week timeframe. Using Surf-PMCA we evaluated the performance of several reference and commercially available prion-specific decontamination procedures. Surprisingly, we found the efficiency of several marketed reagents to remove human vCJD PrPTSE was lower than expected. Overall, our results demonstrate that Surf-PMCA can be used as a rapid and ultrasensitive assay for the detection of human vCJD PrPTSE adsorbed onto a metallic surface, therefore facilitating the development and validation of decontamination procedures against human prions.

  18. Rapid and Highly Sensitive Detection of Variant Creutzfeldt-Jakob Disease Abnormal Prion Protein on Steel Surfaces by Protein Misfolding Cyclic Amplification: Application to Prion Decontamination Studies.

    Directory of Open Access Journals (Sweden)

    Maxime Belondrade

    Full Text Available The prevalence of variant Creutzfeldt-Jakob disease (vCJD in the population remains uncertain, although it has been estimated that 1 in 2000 people in the United Kingdom are positive for abnormal prion protein (PrPTSE by a recent survey of archived appendix tissues. The prominent lymphotropism of vCJD prions raises the possibility that some surgical procedures may be at risk of iatrogenic vCJD transmission in healthcare facilities. It is therefore vital that decontamination procedures applied to medical devices before their reprocessing are thoroughly validated. A current limitation is the lack of a rapid model permissive to human prions. Here, we developed a prion detection assay based on protein misfolding cyclic amplification (PMCA technology combined with stainless-steel wire surfaces as carriers of prions (Surf-PMCA. This assay allowed the specific detection of minute quantities (10-8 brain dilution of either human vCJD or ovine scrapie PrPTSE adsorbed onto a single steel wire, within a two week timeframe. Using Surf-PMCA we evaluated the performance of several reference and commercially available prion-specific decontamination procedures. Surprisingly, we found the efficiency of several marketed reagents to remove human vCJD PrPTSE was lower than expected. Overall, our results demonstrate that Surf-PMCA can be used as a rapid and ultrasensitive assay for the detection of human vCJD PrPTSE adsorbed onto a metallic surface, therefore facilitating the development and validation of decontamination procedures against human prions.

  19. Rapid and Highly Sensitive Detection of Variant Creutzfeldt-Jakob Disease Abnormal Prion Protein on Steel Surfaces by Protein Misfolding Cyclic Amplification: Application to Prion Decontamination Studies.

    Science.gov (United States)

    Belondrade, Maxime; Nicot, Simon; Béringue, Vincent; Coste, Joliette; Lehmann, Sylvain; Bougard, Daisy

    2016-01-01

    The prevalence of variant Creutzfeldt-Jakob disease (vCJD) in the population remains uncertain, although it has been estimated that 1 in 2000 people in the United Kingdom are positive for abnormal prion protein (PrPTSE) by a recent survey of archived appendix tissues. The prominent lymphotropism of vCJD prions raises the possibility that some surgical procedures may be at risk of iatrogenic vCJD transmission in healthcare facilities. It is therefore vital that decontamination procedures applied to medical devices before their reprocessing are thoroughly validated. A current limitation is the lack of a rapid model permissive to human prions. Here, we developed a prion detection assay based on protein misfolding cyclic amplification (PMCA) technology combined with stainless-steel wire surfaces as carriers of prions (Surf-PMCA). This assay allowed the specific detection of minute quantities (10-8 brain dilution) of either human vCJD or ovine scrapie PrPTSE adsorbed onto a single steel wire, within a two week timeframe. Using Surf-PMCA we evaluated the performance of several reference and commercially available prion-specific decontamination procedures. Surprisingly, we found the efficiency of several marketed reagents to remove human vCJD PrPTSE was lower than expected. Overall, our results demonstrate that Surf-PMCA can be used as a rapid and ultrasensitive assay for the detection of human vCJD PrPTSE adsorbed onto a metallic surface, therefore facilitating the development and validation of decontamination procedures against human prions. PMID:26800081

  20. FATE AND TRANSPORT OF PRIONS FROM CHRONIC WASTING DISEASE (CWD) WASTE IN MUNICIPAL SOLID WASTE LANDFILLS

    Science.gov (United States)

    CWD is a fatal neurologic disease of deer and elk caused by an infectious abnormal protein called a prion. Infected free-ranging or captive deer and elk have been found in several states including Wisconsin, Illinois and Minnesota in Region 5. The management of CWD may call for...

  1. Infectivity versus Seeding in Neurodegenerative Diseases Sharing a Prion-Like Mechanism

    Directory of Open Access Journals (Sweden)

    Natalia Fernández-Borges

    2013-01-01

    Full Text Available Prions are considered the best example to prove that the biological information can be transferred protein to protein through a conformational change. The term “prion-like” is used to describe molecular mechanisms that share similarities with the mammalian prion protein self-perpetuating aggregation and spreading characteristics. Since prions are presumably composed only of protein and are infectious, the more similar the mechanisms that occur in the different neurodegenerative diseases, the more these processes will resemble an infection. In vitro and in vivo experiments carried out during the last decade in different neurodegenerative disorders such as Alzheimer's disease (AD, Parkinson's diseases (PD, and amyotrophic lateral sclerosis (ALS have shown a convergence toward a unique mechanism of misfolded protein propagation. In spite of the term “infection” that could be used to explain the mechanism governing the diversity of the pathological processes, other concepts as “seeding” or “de novo induction” are being used to describe the in vivo propagation and transmissibility of misfolded proteins. The current studies are demanding an extended definition of “disease-causing agents” to include those already accepted as well as other misfolded proteins. In this new scenario, “seeding” would be a type of mechanism by which an infectious agent can be transmitted but should not be used to define a whole “infection” process.

  2. Prions and prion-like proteins.

    Science.gov (United States)

    Fraser, Paul E

    2014-07-18

    Prions are self-replicating protein aggregates and are the primary causative factor in a number of neurological diseases in mammals. The prion protein (PrP) undergoes a conformational transformation leading to aggregation into an infectious cellular pathogen. Prion-like protein spreading and transmission of aggregates between cells have also been demonstrated for other proteins associated with Alzheimer disease and Parkinson disease. This protein-only phenomenon may therefore have broader implications in neurodegenerative disorders. The minireviews in this thematic series highlight the recent advances in prion biology and the roles these unique proteins play in disease.

  3. Prion replication occurs in endogenous adult neural stem cells and alters their neuronal fate: involvement of endogenous neural stem cells in prion diseases.

    Directory of Open Access Journals (Sweden)

    Aroa Relaño-Ginès

    Full Text Available Prion diseases are irreversible progressive neurodegenerative diseases, leading to severe incapacity and death. They are characterized in the brain by prion amyloid deposits, vacuolisation, astrocytosis, neuronal degeneration, and by cognitive, behavioural and physical impairments. There is no treatment for these disorders and stem cell therapy therefore represents an interesting new approach. Gains could not only result from the cell transplantation, but also from the stimulation of endogenous neural stem cells (NSC or by the combination of both approaches. However, the development of such strategies requires a detailed knowledge of the pathology, particularly concerning the status of the adult neurogenesis and endogenous NSC during the development of the disease. During the past decade, several studies have consistently shown that NSC reside in the adult mammalian central nervous system (CNS and that adult neurogenesis occurs throughout the adulthood in the subventricular zone of the lateral ventricle or the Dentate Gyrus of the hippocampus. Adult NSC are believed to constitute a reservoir for neuronal replacement during normal cell turnover or after brain injury. However, the activation of this system does not fully compensate the neuronal loss that occurs during neurodegenerative diseases and could even contribute to the disease progression. We investigated here the status of these cells during the development of prion disorders. We were able to show that NSC accumulate and replicate prions. Importantly, this resulted in the alteration of their neuronal fate which then represents a new pathologic event that might underlie the rapid progression of the disease.

  4. Modeling routes of chronic wasting disease transmission: Environmental prion persistence promotes deer population decline and extinction

    Science.gov (United States)

    Almberg, Emily S.; Cross, Paul C.; Johnson, Christopher J.; Heisey, Dennis M.; Richards, Bryan J.

    2011-01-01

    Chronic wasting disease (CWD) is a fatal disease of deer, elk, and moose transmitted through direct, animal-to-animal contact, and indirectly, via environmental contamination. Considerable attention has been paid to modeling direct transmission, but despite the fact that CWD prions can remain infectious in the environment for years, relatively little information exists about the potential effects of indirect transmission on CWD dynamics. In the present study, we use simulation models to demonstrate how indirect transmission and the duration of environmental prion persistence may affect epidemics of CWD and populations of North American deer. Existing data from Colorado, Wyoming, and Wisconsin's CWD epidemics were used to define plausible short-term outcomes and associated parameter spaces. Resulting long-term outcomes range from relatively low disease prevalence and limited host-population decline to host-population collapse and extinction. Our models suggest that disease prevalence and the severity of population decline is driven by the duration that prions remain infectious in the environment. Despite relatively low epidemic growth rates, the basic reproductive number, R0, may be much larger than expected under the direct-transmission paradigm because the infectious period can vastly exceed the host's life span. High prion persistence is expected to lead to an increasing environmental pool of prions during the early phases (i.e. approximately during the first 50 years) of the epidemic. As a consequence, over this period of time, disease dynamics will become more heavily influenced by indirect transmission, which may explain some of the observed regional differences in age and sex-specific disease patterns. This suggests management interventions, such as culling or vaccination, will become increasingly less effective as CWD epidemics progress.

  5. The Use of Monoclonal Antibodies in Human Prion Disease

    Science.gov (United States)

    Bodemer, Walter

    Detection of PrP and its pathological isoform(s) is the key to understanding the etiology and pathogenesis of transmissible spongiform encephalopathy. There is ample evidence that PrP isoforms constitute a major component of an unknown and perhaps unconventional infectious agent. An etiological relationship between human and zoonotic transmissible spongiform encephalopathies may be revealed with monoclonal antibodies. Knowledge of the conformational transition rendering a nonpathogenic, almost ubiquitous cellular protein into a pathogenic one is crucial to defining pathomechanisms. The stepwise or even continuous formation of pathogenic molecules can be monitored. Any improvement in the early diagnosis could help to conceive new therapeutic measures which are not currently available. Determination of PrP isoforms in tissue, cells, or body fluids may be of prognostic value. Many experimental approaches in molecular medicine and molecular biology of the prion protein already rely on monoclonal antibodies. Recombinant antibodies such as the single-chain Fv may soon replace traditional hybridoma techniques. Binding affinity can easily be manipulated by a number of techniques, including in vitro mutagenesis - a step which could never be carried out using the traditional hybridoma technology. Monoclonal antibodies are and will remain an essential support for ongoing research on the prion protein in general and on the unconventional infectious prions.

  6. Metabolism of minor isoforms of prion proteins Cytosolic prion protein and transmembrane prion protein*

    Institute of Scientific and Technical Information of China (English)

    Zhiqi Song; Deming Zhao; Lifeng Yang

    2013-01-01

    Transmissible spongiform encephalopathy or prion disease is triggered by the conversion from cellular prion protein to pathogenic prion protein. Growing evidence has concentrated on prion protein configuration changes and their correlation with prion disease transmissibility and pathoge-nicity. In vivo and in vitro studies have shown that several cytosolic forms of prion protein with spe-cific topological structure can destroy intracellular stability and contribute to prion protein pathoge-nicity. In this study, the latest molecular chaperone system associated with endoplasmic reticu-lum-associated protein degradation, the endoplasmic reticulum resident protein quality-control system and the ubiquitination proteasome system, is outlined. The molecular chaperone system directly correlates with the prion protein degradation pathway. Understanding the molecular me-chanisms wil help provide a fascinating avenue for further investigations on prion disease treatment and prion protein-induced neurodegenerative diseases.

  7. Mathematical models for the diffusion magnetic resonance signal abnormality in patients with prion diseases

    Directory of Open Access Journals (Sweden)

    Matteo Figini

    2015-01-01

    Full Text Available In clinical practice signal hyperintensity in the cortex and/or in the striatum on magnetic resonance (MR diffusion-weighted images (DWIs is a marker of sporadic Creutzfeldt–Jakob Disease (sCJD. MR diagnostic accuracy is greater than 90%, but the biophysical mechanisms underpinning the signal abnormality are unknown. The aim of this prospective study is to combine an advanced DWI protocol with new mathematical models of the microstructural changes occurring in prion disease patients to investigate the cause of MR signal alterations. This underpins the later development of more sensitive and specific image-based biomarkers. DWI data with a wide a range of echo times and diffusion weightings were acquired in 15 patients with suspected diagnosis of prion disease and in 4 healthy age-matched subjects. Clinical diagnosis of sCJD was made in nine patients, genetic CJD in one, rapidly progressive encephalopathy in three, and Gerstmann–Sträussler–Scheinker syndrome in two. Data were analysed with two bi-compartment models that represent different hypotheses about the histopathological alterations responsible for the DWI signal hyperintensity. A ROI-based analysis was performed in 13 grey matter areas located in affected and apparently unaffected regions from patients and healthy subjects. We provide for the first time non-invasive estimate of the restricted compartment radius, designed to reflect vacuole size, which is a key discriminator of sCJD subtypes. The estimated vacuole size in DWI hyperintense cortex was in the range between 3 and 10 µm that is compatible with neuropathology measurements. In DWI hyperintense grey matter of sCJD patients the two bi-compartment models outperform the classic mono-exponential ADC model. Both new models show that T2 relaxation times significantly increase, fast and slow diffusivities reduce, and the fraction of the compartment with slow/restricted diffusion increases compared to unaffected grey matter of

  8. Sheep scrapie susceptibility-linked polymorphisms do not modulate the initial binding of cellular to disease-associated prion protein prior to conversion

    NARCIS (Netherlands)

    Rigter, A.; Bossers, A.

    2005-01-01

    Conversion of the host-encoded protease-sensitive cellular prion protein (PrPC) into the scrapie-associated protease-resistant isoform (PrPSc) of prion protein (PrP) is the central event in transmissible spongiform encephalopathies or prion diseases. Differences in transmissibility and susceptibilit

  9. A brief history of prions.

    Science.gov (United States)

    Zabel, Mark D; Reid, Crystal

    2015-12-01

    Proteins were described as distinct biological molecules and their significance in cellular processes was recognized as early as the 18th century. At the same time, Spanish shepherds observed a disease that compelled their Merino sheep to pathologically scrape against fences, a defining clinical sign that led to the disease being named scrapie. In the late 19th century, Robert Koch published his postulates for defining causative agents of disease. In the early 20th century, pathologists Creutzfeldt and Jakob described a neurodegenerative disease that would later be included with scrapie into a group of diseases known as transmissible spongiform encephalopathies (TSEs). Later that century, mounting evidence compelled a handful of scientists to betray the prevailing biological dogma governing pathogen replication that Watson and Crick so convincingly explained by cracking the genetic code just two decades earlier. Because TSEs seemed to defy these new rules, J.S. Griffith theorized mechanisms by which a pathogenic protein could encipher its own replication blueprint without a genetic code. Stanley Prusiner called this proteinaceous infectious pathogen a prion. Here we offer a concise account of the discovery of prions, the causative agent of TSEs, in the wider context of protein biochemistry and infectious disease. We highlight the discovery of prions in yeast and discuss the implication of prions as epigenomic carriers of biological and pathological information. We also consider expanding the prion hypothesis to include other proteins whose alternate isoforms confer new biological or pathological properties.

  10. Molecular Mechanisms in the Pathogenesis of Alzheimer’s disease and Tauopathies-Prion-Like Seeded Aggregation and Phosphorylation

    Science.gov (United States)

    Hasegawa, Masato

    2016-01-01

    Neurofibrillary tau pathology (tangles and threads) and extracellular amyloid-β (Aβ) pathology are defining features of Alzheimer’s disease. For 25 years, most research has focused on the amyloid hypothesis of AD pathogenesis and progression. But, because of failures in clinical trials of Aβ-targeted therapies and the new concept of prion-like propagation of intracellular abnormal proteins, tau has come back into the spotlight as a candidate therapeutic target in AD. Tau pathologies are found in a range of neurodegenerative disorders, but extensive analyses of pathological tau in diseased brains has demonstrated that the abnormal tau protein in each disease is structurally distinct, supporting the idea that progression of the diverse but characteristic tau pathologies occurs through prion-like seed-dependent aggregation. Therefore, intervention in the conversion of normal tau to abnormal forms and in cell-to-cell transmission of tau may be the key to development of disease-modifying therapies for AD and other dementing disorders. PMID:27136595

  11. Chaperoning prions: the story unfolds

    OpenAIRE

    O'Connor, David; Jones, Gary

    2006-01-01

    Prions are infectious proteins that are responsible for a number of mammalian degenerative diseases. The discovery of prions in yeast has allowed detailed genetic analysis to be carried out to identify cellular factors involved in prion propagation. It is now clear that a complex relationship exists between molecular chaperones and prion propagation. Prions may actually have evolved to exploit the cell's chaperone machinery to ensure their own propaga...

  12. Structural Determinants of Phenotypic Diversity and Replication Rate of Human Prions

    OpenAIRE

    Safar, Jiri G; Xiangzhu Xiao; Kabir, Mohammad E.; Shugui Chen; Chae Kim; Tracy Haldiman; Yvonne Cohen; Wei Chen; Cohen, Mark L.; Surewicz, Witold K.

    2015-01-01

    Author Summary Sporadic Creutzfeldt-Jakob disease (sCJD) represents ~90% of all human prion diseases worldwide. This neurodegenerative disease, which is transmissible and invariably fatal, is characterized by variable progression rates and remarkable diversity of clinical and pathological traits. The infectious sCJD prions propagating the pathology mainly in the brain are assemblies of abnormally folded isoform (PrPSc) of a host-encoded prion protein (PrPC). The structure and replication mech...

  13. Positive 14-3-3 and tau proteins in a sporadic Creutzfeldt-Jakob disease case and a brief perspective of prion diseases in Colombia.

    Science.gov (United States)

    Escandón-Vargas, Kevin; Zorrilla-Vaca, Andrés; Corral-Prado, Raúl Heli

    2016-01-01

    Prion diseases are rare neurodegenerative disorders occurring worldwide and affecting both humans and animals. Herein, we present the case of a patient diagnosed with definite sporadic Creutzfeldt-Jakob disease in Cali, Colombia. Besides neurological examination, 14-3-3 and tau proteins were valuable tools supporting the diagnosis. We also present a brief perspective of the prion diseases reported in Colombia to date. Although the incidence of prion diseases is unknown in Colombia, our literature review revealed that one case of scrapie in 1981 and 29 human sporadic cases of Creutzfeldt-Jakob disease have been documented and published in our country. PMID:27622622

  14. Diffusion versus network models as descriptions for the spread of prion diseases in the brain.

    Science.gov (United States)

    Matthäus, Franziska

    2006-05-01

    In this paper we will discuss different modeling approaches for the spread of prion diseases in the brain. Firstly, we will compare reaction-diffusion models with models of epidemic diseases on networks. The solutions of the resulting reaction-diffusion equations exhibit traveling wave behavior on a one-dimensional domain, and the wave speed can be estimated. The models can be tested for diffusion-driven (Turing) instability, which could present a possible mechanism for the formation of plaques. We also show that the reaction-diffusion systems are capable of reproducing experimental data on prion spread in the mouse visual system. Secondly, we study classical epidemic models on networks, and use these models to study the influence of the network topology on the disease progression. PMID:16219329

  15. MM2-thalamic Creutzfeldt-Jakob disease: neuropathological, biochemical and transmission studies identify a distinctive prion strain.

    Science.gov (United States)

    Moda, Fabio; Suardi, Silvia; Di Fede, Giuseppe; Indaco, Antonio; Limido, Lucia; Vimercati, Chiara; Ruggerone, Margherita; Campagnani, Ilaria; Langeveld, Jan; Terruzzi, Alessandro; Brambilla, Antonio; Zerbi, Pietro; Fociani, Paolo; Bishop, Matthew T; Will, Robert G; Manson, Jean C; Giaccone, Giorgio; Tagliavini, Fabrizio

    2012-09-01

    In Creutzfeldt-Jakob disease (CJD), molecular typing based on the size of the protease resistant core of the disease-associated prion protein (PrP(Sc) ) and the M/V polymorphism at codon 129 of the PRNP gene correlates with the clinico-pathologic subtypes. Approximately 95% of the sporadic 129MM CJD patients are characterized by cerebral deposition of type 1 PrP(Sc) and correspond to the classic clinical CJD phenotype. The rare 129MM CJD patients with type 2 PrP(Sc) are further subdivided in a cortical and a thalamic form also indicated as sporadic fatal insomnia. We observed two young patients with MM2-thalamic CJD. Main neuropathological features were diffuse, synaptic PrP immunoreactivity in the cerebral cortex and severe neuronal loss and gliosis in the thalamus and olivary nucleus. Western blot analysis showed the presence of type 2A PrP(Sc) . Challenge of transgenic mice expressing 129MM human PrP showed that MM2-thalamic sporadic CJD (sCJD) was able to transmit the disease, at variance with MM2-cortical sCJD. The affected mice showed deposition of type 2A PrP(Sc) , a scenario that is unprecedented in this mouse line. These data indicate that MM2-thalamic sCJD is caused by a prion strain distinct from the other sCJD subtypes including the MM2-cortical form. PMID:22288561

  16. MM2-thalamic Creutzfeldt-Jakob disease: neuropathological, biochemical and transmission studies identify a distinctive prion strain.

    Science.gov (United States)

    Moda, Fabio; Suardi, Silvia; Di Fede, Giuseppe; Indaco, Antonio; Limido, Lucia; Vimercati, Chiara; Ruggerone, Margherita; Campagnani, Ilaria; Langeveld, Jan; Terruzzi, Alessandro; Brambilla, Antonio; Zerbi, Pietro; Fociani, Paolo; Bishop, Matthew T; Will, Robert G; Manson, Jean C; Giaccone, Giorgio; Tagliavini, Fabrizio

    2012-09-01

    In Creutzfeldt-Jakob disease (CJD), molecular typing based on the size of the protease resistant core of the disease-associated prion protein (PrP(Sc) ) and the M/V polymorphism at codon 129 of the PRNP gene correlates with the clinico-pathologic subtypes. Approximately 95% of the sporadic 129MM CJD patients are characterized by cerebral deposition of type 1 PrP(Sc) and correspond to the classic clinical CJD phenotype. The rare 129MM CJD patients with type 2 PrP(Sc) are further subdivided in a cortical and a thalamic form also indicated as sporadic fatal insomnia. We observed two young patients with MM2-thalamic CJD. Main neuropathological features were diffuse, synaptic PrP immunoreactivity in the cerebral cortex and severe neuronal loss and gliosis in the thalamus and olivary nucleus. Western blot analysis showed the presence of type 2A PrP(Sc) . Challenge of transgenic mice expressing 129MM human PrP showed that MM2-thalamic sporadic CJD (sCJD) was able to transmit the disease, at variance with MM2-cortical sCJD. The affected mice showed deposition of type 2A PrP(Sc) , a scenario that is unprecedented in this mouse line. These data indicate that MM2-thalamic sCJD is caused by a prion strain distinct from the other sCJD subtypes including the MM2-cortical form.

  17. Infectivity-associated PrP(Sc) and disease duration-associated PrP(Sc) of mouse BSE prions.

    Science.gov (United States)

    Miyazawa, Kohtaro; Okada, Hiroyuki; Masujin, Kentaro; Iwamaru, Yoshifumi; Yokoyama, Takashi

    2015-01-01

    Disease-related prion protein (PrP(Sc)), which is a structural isoform of the host-encoded cellular prion protein, is thought to be a causative agent of transmissible spongiform encephalopathies. However, the specific role of PrP(Sc) in prion pathogenesis and its relationship to infectivity remain controversial. A time-course study of prion-affected mice was conducted, which showed that the prion infectivity was not simply proportional to the amount of PrP(Sc) in the brain. Centrifugation (20,000 ×g) of the brain homogenate showed that most of the PrP(Sc) was precipitated into the pellet, and the supernatant contained only a slight amount of PrP(Sc). Interestingly, mice inoculated with the obtained supernatant showed incubation periods that were approximately 15 d longer than those of mice inoculated with the crude homogenate even though both inocula contained almost the same infectivity. Our results suggest that a small population of fine PrP(Sc) may be responsible for prion infectivity and that large, aggregated PrP(Sc) may contribute to determining prion disease duration.

  18. Prions in the Urine of Patients with Variant Creutzfeldt–Jakob Disease

    Science.gov (United States)

    Moda, Fabio; Gambetti, Pierluigi; Notari, Silvio; Concha-Marambio, Luis; Catania, Marcella; Park, Kyung-Won; Maderna, Emanuela; Suardi, Silvia; Haïk, Stéphane; Brandel, Jean-Philippe; Ironside, James; Knight, Richard; Tagliavini, Fabrizio; Soto, Claudio

    2014-01-01

    BACKGROUND Prions, the infectious agents responsible for transmissible spongiform encephalopathies, consist mainly of the misfolded prion protein (PrPSc). The unique mechanism of transmission and the appearance of a variant form of Creutzfeldt–Jakob disease, which has been linked to consumption of prion-contaminated cattle meat, have raised concerns about public health. Evidence suggests that variant Creutzfeldt–Jakob disease prions circulate in body fluids from people in whom the disease is silently incubating. METHODS To investigate whether PrPSc can be detected in the urine of patients with variant Creutzfeldt–Jakob disease, we used the protein misfolding cyclic amplification (PMCA) technique to amplify minute quantities of PrPSc, enabling highly sensitive detection of the protein. We analyzed urine samples from several patients with various transmissible spongiform encephalopathies (variant and sporadic Creutzfeldt–Jakob disease and genetic forms of prion disease), patients with other degenerative or nondegenerative neurologic disorders, and healthy persons. RESULTS PrPSc was detectable only in the urine of patients with variant Creutzfeldt–Jakob disease and had the typical electrophoretic profile associated with this disease. PrPSc was detected in 13 of 14 urine samples obtained from patients with variant Creutzfeldt–Jakob disease and in none of the 224 urine samples obtained from patients with other neurologic diseases and from healthy controls, resulting in an estimated sensitivity of 92.9% (95% confidence interval [CI], 66.1 to 99.8) and a specificity of 100.0% (95% CI, 98.4 to 100.0). The PrPSc concentration in urine calculated by means of quantitative PMCA was estimated at 1×10−16 g per milliliter, or 3×10−21 mol per milliliter, which extrapolates to approximately 40 to 100 oligomeric particles of PrPSc per milliliter of urine. CONCLUSIONS Urine samples obtained from patients with variant Creutzfeldt–Jakob disease contained minute

  19. Early detection of abnormal prion protein in genetic human prion diseases now possible using real-time QUIC assay.

    Directory of Open Access Journals (Sweden)

    Kazunori Sano

    Full Text Available INTRODUCTION: The definitive diagnosis of genetic prion diseases (gPrD requires pathological confirmation. To date, diagnosis has relied upon the finding of the biomarkers 14-3-3 protein and total tau (t-tau protein in the cerebrospinal fluid (CSF, but many researchers have reported that these markers are not sufficiently elevated in gPrD, especially in Gerstmann-Sträussler-Scheinker syndrome (GSS. We recently developed a new in vitro amplification technology, designated "real-time quaking-induced conversion (RT-QUIC", to detect the abnormal form of prion protein in CSF from sporadic Creutzfeldt-Jakob disease (sCJD patients. In the present study, we aimed to investigate the presence of biomarkers and evaluate RT-QUIC assay in patients with gPrD, as the utility of RT-QUIC as a diagnostic tool in gPrD has yet to be determined. METHOD/PRINCIPAL FINDINGS: 56 CSF samples were obtained from gPrD patients, including 20 cases of GSS with P102L mutation, 12 cases of fatal familial insomnia (FFI; D178N, and 24 cases of genetic CJD (gCJD, comprising 22 cases with E200K mutation and 2 with V203I mutation. We subjected all CSF samples to RT-QUIC assay, analyzed 14-3-3 protein by Western blotting, and measured t-tau protein using an ELISA kit. The detection sensitivities of RT-QUIC were as follows: GSS (78%, FFI (100%, gCJD E200K (87%, and gCJD V203I (100%. On the other hand the detection sensitivities of biomarkers were considerably lower: GSS (11%, FFI (0%, gCJD E200K (73%, and gCJD V203I (67%. Thus, RT-QUIC had a much higher detection sensitivity compared with testing for biomarkers, especially in patients with GSS and FFI. CONCLUSION/SIGNIFICANCE: RT-QUIC assay is more sensitive than testing for biomarkers in gPrD patients. RT-QUIC method would thus be useful as a diagnostic tool when the patient or the patient's family does not agree to genetic testing, or to confirm the diagnosis in the presence of a positive result for genetic testing.

  20. Serial MRI in early Creutzfeldt-Jacob disease with a point mutation of prion protein at codon 180

    International Nuclear Information System (INIS)

    We report a 66-year-old woman with histologically diagnosed Creutzfeld-Jacob disease (CJD), followed with MRI from an early clinical stage. MRI demonstrated expansion of the high cortical signal on T2-weighted images, which differs from previous MRI reports of CJD. This patient followed an atypical clinical course: 16 months had passed before she developed akinetic mutism, and periodic sharp waves had not been detected on EEG after 2 years in spite of her akinetic mutism. Brain biopsy showed primary spongiform changes in the grey matter, and a point mutation of the prion protein gene at codon 180 was discovered using polymerase chain reaction direct sequencing and Tth 111 I cutting. This is the first case with the point mutation of the codon 180 variant with an atypical clinical course and characteristic MRI findings. (orig.)

  1. Survey of public perceptions of prion disease risks in Canada: what does the public care about?

    Science.gov (United States)

    Lemyre, L; Gibson, S; Markon, M P L; Lee, J E C; Brazeau, I; Carroll, A; Boutette, P; Krewski, D

    2009-01-01

    A national public survey on public perceptions of prion disease risk in Canada was conducted from October to December 2007. The survey aimed at documenting the public's perceptions of prion diseases, within the broader context of food safety, in establishing parameters of risk acceptability. It also documented the public's perceptions of prion diseases in delineating social values and ethics that can guide Canada's future policies on prion disease risk management. In addition, the survey served to establish baseline data against which to monitor the evolution of the public's views on and understanding of this important risk issue. In total, 1517 Canadians were randomly selected to be representative of the adult population by region, age, and gender, as per the 2001 Census. This study presents descriptive findings from the survey regarding perceived risk, perceived control, uncertainty, sources of information, trust and knowledge, and beliefs pertaining to bovine spongiform encephalopathy (BSE). The survey data reveal that Canadians do not perceive mad cow disease as a salient risk but consider it more of an economic, political, social, and foreign trade issue than a public health one. Canadians are somewhat prepared to pay a premium to have a safer food supply, but not to the same extent that they desire extra measures pertaining to BSE risk management. In the context of increasing accountability in risk management decisions about food safety and population health issues, it is important to understand the way Canadians perceive such matters and identify their information needs and the factors that influence the acceptability of risks and of risk management policies. PMID:19697248

  2. Prion疾病疫苗研究策略%Strategies of Vaccines against Prion Disease

    Institute of Scientific and Technical Information of China (English)

    郭燕; 董小平

    2009-01-01

    朊病毒病是一类侵袭人类及多种动物中枢神经系统的致死性退行性脑病,目前缺乏有效的预防和治疗方法.朊病毒病的重组蛋白亚单位疫苗、DNA疫苗、合成肽疫苗、病毒样颗粒疫苗、树突状细胞疫苗、黏膜免疫疫苗等已取得一定进展,但现有的免疫策略仅能部分克服免疫耐受,诱导较低或中等滴度的抗体,对PrP~(Sc)感染动物模型只能提供部分保护,Prion疫苗研究任重而道远.%Prion diseases are fatal neurodegenerative disorders which can be acquired by human and many kinds of animals.At present,there are no effective preventive and therapeutic methods.Recombinant protein subunit vaccine,DNA vaccine,synthetic peptide vaccine,viral like particles,dendritic cell vaccine and musocal vaccine against Prion diseases have achieved certain progress.However,strategies used now can only partially overcome immune tolerance,induce only low and moderate degree of antibody,and provide inadequate protection in animal models.Therefore,strategy of vaccines against Prion diseases is thorny but imminent.

  3. Brain delivery of AAV9 expressing an anti-PrP monovalent antibody delays prion disease in mice.

    Science.gov (United States)

    Moda, Fabio; Vimercati, Chiara; Campagnani, Ilaria; Ruggerone, Margherita; Giaccone, Giorgio; Morbin, Michela; Zentilin, Lorena; Giacca, Mauro; Zucca, Ileana; Legname, Giuseppe; Tagliavini, Fabrizio

    2012-01-01

    Prion diseases are caused by a conformational modification of the cellular prion protein (PrP (C)) into disease-specific forms, termed PrP (Sc), that have the ability to interact with PrP (C) promoting its conversion to PrP (Sc). In vitro studies demonstrated that anti-PrP antibodies inhibit this process. In particular, the single chain variable fragment D18 antibody (scFvD18) showed high efficiency in curing chronically prion-infected cells. This molecule binds the PrP (C) region involved in the interaction with PrP (Sc) thus halting further prion formation. These findings prompted us to test the efficiency of scFvD18 in vivo. A recombinant Adeno-Associated Viral vector serotype 9 was used to deliver scFvD18 to the brain of mice that were subsequently infected by intraperitoneal route with the mouse-adapted scrapie strain RML. We found that the treatment was safe, prolonged the incubation time of scrapie-infected animals and decreased the burden of total proteinase-resistant PrP (Sc) in the brain, suggesting that scFvD18 interferes with prion replication in vivo. This approach is relevant for designing new therapeutic strategies for prion diseases and other disorders characterized by protein misfolding. PMID:22842862

  4. Brain delivery of AAV9 expressing an anti-PrP monovalent antibody delays prion disease in mice.

    Science.gov (United States)

    Moda, Fabio; Vimercati, Chiara; Campagnani, Ilaria; Ruggerone, Margherita; Giaccone, Giorgio; Morbin, Michela; Zentilin, Lorena; Giacca, Mauro; Zucca, Ileana; Legname, Giuseppe; Tagliavini, Fabrizio

    2012-01-01

    Prion diseases are caused by a conformational modification of the cellular prion protein (PrP (C)) into disease-specific forms, termed PrP (Sc), that have the ability to interact with PrP (C) promoting its conversion to PrP (Sc). In vitro studies demonstrated that anti-PrP antibodies inhibit this process. In particular, the single chain variable fragment D18 antibody (scFvD18) showed high efficiency in curing chronically prion-infected cells. This molecule binds the PrP (C) region involved in the interaction with PrP (Sc) thus halting further prion formation. These findings prompted us to test the efficiency of scFvD18 in vivo. A recombinant Adeno-Associated Viral vector serotype 9 was used to deliver scFvD18 to the brain of mice that were subsequently infected by intraperitoneal route with the mouse-adapted scrapie strain RML. We found that the treatment was safe, prolonged the incubation time of scrapie-infected animals and decreased the burden of total proteinase-resistant PrP (Sc) in the brain, suggesting that scFvD18 interferes with prion replication in vivo. This approach is relevant for designing new therapeutic strategies for prion diseases and other disorders characterized by protein misfolding.

  5. Intranasal inoculation of white-tailed deer (Odocoileus virginianus with lyophilized chronic wasting disease prion particulate complexed to montmorillonite clay.

    Directory of Open Access Journals (Sweden)

    Tracy A Nichols

    Full Text Available Chronic wasting disease (CWD, the only known prion disease endemic in wildlife, is a persistent problem in both wild and captive North American cervid populations. This disease continues to spread and cases are found in new areas each year. Indirect transmission can occur via the environment and is thought to occur by the oral and/or intranasal route. Oral transmission has been experimentally demonstrated and although intranasal transmission has been postulated, it has not been tested in a natural host until recently. Prions have been shown to adsorb strongly to clay particles and upon oral inoculation the prion/clay combination exhibits increased infectivity in rodent models. Deer and elk undoubtedly and chronically inhale dust particles routinely while living in the landscape while foraging and rutting. We therefore hypothesized that dust represents a viable vehicle for intranasal CWD prion exposure. To test this hypothesis, CWD-positive brain homogenate was mixed with montmorillonite clay (Mte, lyophilized, pulverized and inoculated intranasally into white-tailed deer once a week for 6 weeks. Deer were euthanized at 95, 105, 120 and 175 days post final inoculation and tissues examined for CWD-associated prion proteins by immunohistochemistry. Our results demonstrate that CWD can be efficiently transmitted utilizing Mte particles as a prion carrier and intranasal exposure.

  6. Techniques to elucidate the conformation of prions

    OpenAIRE

    Daus, Martin L.

    2015-01-01

    Proteinaceous infectious particles (prions) are unique pathogens as they are devoid of any coding nucleic acid. Whilst it is assumed that prion disease is transmitted by a misfolded isoform of the cellular prion protein, the structural insight of prions is still vague and research for high resolution structural information of prions is still ongoing. In this review, techniques that may contribute to the clarification of the conformation of prions are presented and discussed.

  7. Techniques to elucidate the conformation of prions

    Institute of Scientific and Technical Information of China (English)

    Martin; L; Daus

    2015-01-01

    Proteinaceous infectious particles(prions) are unique pathogens as they are devoid of any coding nucleic acid.Whilst it is assumed that prion disease is transmitted by a misfolded isoform of the cellular prion protein, the structural insight of prions is still vague and research for high resolution structural information of prions is still ongoing. In this review, techniques that may contribute to the clarification of the conformation of prions are presented and discussed.

  8. Pentosan polysulfate as a prophylactic and therapeutic agent against prion disease.

    Science.gov (United States)

    Dealler, Stephen; Rainov, Nikolai G

    2003-05-01

    Pentosan polysulfate (PPS) acts by imitating the physiological roles of the heparans. It binds to heparan binding sites on proteins and alters the physiological actions of these proteins. PPS acts as a prophylactic agent against infection with prions both in vivo and in vitro. Low concentrations (10 mg/ml) are needed extracellularly for this effect to be seen but, due to cellular uptake, it is believed that a much higher concentration is found intracellularly. The prophylactic effect of PPS is observed if the drug is administered to mice between 3 months before and approximately 30 days after the inoculation of the disease. After that point it is considered that the infection has entered the nervous system, and that the drug cannot penetrate the blood-brain barrier. The prophylaxis of humans with oral PPS and the current therapeutic activity of the drug when given by intracerebroventricular infusion to symptomatic, prion-infected animals are discussed.

  9. Estimating prion adsorption capacity of soil by BioAssay of Subtracted Infectivity from Complex Solutions (BASICS.

    Directory of Open Access Journals (Sweden)

    A Christy Wyckoff

    Full Text Available Prions, the infectious agent of scrapie, chronic wasting disease and other transmissible spongiform encephalopathies, are misfolded proteins that are highly stable and resistant to degradation. Prions are known to associate with clay and other soil components, enhancing their persistence and surprisingly, transmissibility. Currently, few detection and quantification methods exist for prions in soil, hindering an understanding of prion persistence and infectivity in the environment. Variability in apparent infectious titers of prions when bound to soil has complicated attempts to quantify the binding capacity of soil for prion infectivity. Here, we quantify the prion adsorption capacity of whole, sandy loam soil (SLS typically found in CWD endemic areas in Colorado; and purified montmorillonite clay (Mte, previously shown to bind prions, by BioAssay of Subtracted Infectivity in Complex Solutions (BASICS. We incubated prion positive 10% brain homogenate from terminally sick mice infected with the Rocky Mountain Lab strain of mouse-adapted prions (RML with 10% SLS or Mte. After 24 hours samples were centrifuged five minutes at 200 × g and soil-free supernatant was intracerebrally inoculated into prion susceptible indicator mice. We used the number of days post inoculation to clinical disease to calculate the infectious titer remaining in the supernatant, which we subtracted from the starting titer to determine the infectious prion binding capacity of SLS and Mte. BASICS indicated SLS bound and removed ≥ 95% of infectivity. Mte bound and removed lethal doses (99.98% of prions from inocula, effectively preventing disease in the mice. Our data reveal significant prion-binding capacity of soil and the utility of BASICS to estimate prion loads and investigate persistence and decomposition in the environment. Additionally, since Mte successfully rescued the mice from prion disease, Mte might be used for remediation and decontamination protocols.

  10. Panencephalopathic Creutzfeldt-Jakob disease with distinct pattern of prion protein deposition in a patient with D178N mutation and homozygosity for valine at codon 129 of the prion protein Gene.

    Science.gov (United States)

    Marcon, Gabriella; Indaco, Antonio; Di Fede, Giuseppe; Suardi, Silvia; Finato, Nicoletta; Moretti, Valentino; Micoli, Sandro; Fociani, Paolo; Zerbi, Pietro; Pincherle, Alessandro; Redaelli, Veronica; Tagliavini, Fabrizio; Giaccone, Giorgio

    2014-03-01

    Prion diseases include sporadic, acquired and genetic forms linked to mutations of the prion protein (PrP) gene (PRNP). In subjects carrying the D178N PRNP mutation, distinct phenotypes can be observed, depending on the methionine/valine codon 129 polymorphism. We present here a 53-year-old woman with D178N mutation in the PRNP gene and homozygosity for valine at codon 129. The disease started at age 47 with memory deficits, progressive cognitive impairment and ataxia. The clinical picture slowly worsened to a state of akinetic mutism in about 2 years and the disease course was 6 years. The neuropathologic examination demonstrated severe diffuse cerebral atrophy with neuronal loss, spongiosis and marked myelin loss and tissue rarefaction in the hemispheric white matter, configuring panencephalopathic Creutzfeldt-Jakob disease. PrP deposition was present in the cerebral cortex, basal ganglia and cerebellum with diffuse synaptic-type pattern of immunoreactivity and clusters of countless, small PrP deposits, particularly evident in the lower cortical layers, in the striatum and in the molecular layer of the cerebellum. Western blot analysis showed the presence of type 1 PrP(Sc) (Parchi classification). These findings underline the clear-cut distinction between the neuropathological features of Creutzfeldt-Jakob disease associated with D178N PRNP mutation and those of fatal familial insomnia.

  11. Limited transcriptional response of ovine microglia to prion accumulation

    Science.gov (United States)

    Sheep scrapie (Sc) is the classical transmissible spongiform encephalopathy (prion disease). The conversion of normal cellular prion protein (PrPC) to disease-associated prion protein (PrPSc) is the fundamental pathogenesis of prion diseases. Many of the molecular mechanisms contributing to prion ...

  12. Prion protein polymorphisms affect chronic wasting disease progression.

    Directory of Open Access Journals (Sweden)

    Chad J Johnson

    Full Text Available Analysis of the PRNP gene in cervids naturally infected with chronic wasting disease (CWD suggested that PRNP polymorphisms affect the susceptibility of deer to infection. To test this effect, we orally inoculated 12 white-tailed deer with CWD agent. Three different PRNP alleles, wild-type (wt; glutamine at amino acid 95 and glycine at 96, Q95H (glutamine to histidine at amino acid position 95 and G96S (glycine to serine at position 96 were represented in the study cohort with 5 wt/wt, 3 wt/G96S, and 1 each wt/Q95H and Q95H/G96S. Two animals were lost to follow-up due to intercurrent disease. The inoculum was prepared from Wisconsin hunter-harvested homozygous wt/wt animals. All infected deer presented with clinical signs of CWD; the orally infected wt/wt had an average survival period of 693 days post inoculation (dpi and G96S/wt deer had an average survival period of 956 dpi. The Q95H/wt and Q95H/G96S deer succumbed to CWD at 1,508 and 1,596 dpi respectively. These data show that polymorphisms in the PRNP gene affect CWD incubation period. Deer heterozygous for the PRNP alleles had extended incubation periods with the Q95H allele having the greatest effect.

  13. Prion protein polymorphisms affect chronic wasting disease progression.

    Science.gov (United States)

    Johnson, Chad J; Herbst, Allen; Duque-Velasquez, Camilo; Vanderloo, Joshua P; Bochsler, Phil; Chappell, Rick; McKenzie, Debbie

    2011-01-01

    Analysis of the PRNP gene in cervids naturally infected with chronic wasting disease (CWD) suggested that PRNP polymorphisms affect the susceptibility of deer to infection. To test this effect, we orally inoculated 12 white-tailed deer with CWD agent. Three different PRNP alleles, wild-type (wt; glutamine at amino acid 95 and glycine at 96), Q95H (glutamine to histidine at amino acid position 95) and G96S (glycine to serine at position 96) were represented in the study cohort with 5 wt/wt, 3 wt/G96S, and 1 each wt/Q95H and Q95H/G96S. Two animals were lost to follow-up due to intercurrent disease. The inoculum was prepared from Wisconsin hunter-harvested homozygous wt/wt animals. All infected deer presented with clinical signs of CWD; the orally infected wt/wt had an average survival period of 693 days post inoculation (dpi) and G96S/wt deer had an average survival period of 956 dpi. The Q95H/wt and Q95H/G96S deer succumbed to CWD at 1,508 and 1,596 dpi respectively. These data show that polymorphisms in the PRNP gene affect CWD incubation period. Deer heterozygous for the PRNP alleles had extended incubation periods with the Q95H allele having the greatest effect.

  14. Prion propagation in vitro: are we there yet?

    OpenAIRE

    Ryou, Chongsuk; Mays, Charles E.

    2008-01-01

    Prion diseases are caused by proteinaceous pathogens termed prions. Although the details of the mechanism of prion propagation are not fully understood, conformational conversion of cellular prion protein (PrPC) to misfolded, disease-associated scrapie prion protein (PrPSc) is considered the essential biochemical event for prion replication. Currently, studying prion replication in vitro is difficult due to the lack of a system which fully recapitulates the in vivo phenomenon. Over the last 1...

  15. Cells and prions: a license to replicate.

    Science.gov (United States)

    Nuvolone, Mario; Aguzzi, Adriano; Heikenwalder, Mathias

    2009-08-20

    Prion diseases are neurodegenerative, infectious disorders characterized by the aggregation of a misfolded isoform of the cellular prion protein (PrP(C)). The infectious agent - termed prion - is mainly composed of misfolded PrP(Sc). In addition to the central nervous system prions can colonize secondary lymphoid organs and inflammatory foci. Follicular dendritic cells are important extraneural sites of prion replication. However, recent data point to a broader range of cell types that can replicate prions. Here, we review the state of the art in regards to peripheral prion replication, neuroinvasion and the determinants of prion replication competence. PMID:19527722

  16. Rapid and Quantitative Assay of Amyloid-Seeding Activity in Human Brains Affected with Prion Diseases.

    Directory of Open Access Journals (Sweden)

    Hanae Takatsuki

    Full Text Available The infectious agents of the transmissible spongiform encephalopathies are composed of amyloidogenic prion protein, PrPSc. Real-time quaking-induced conversion can amplify very small amounts of PrPSc seeds in tissues/body fluids of patients or animals. Using this in vitro PrP-amyloid amplification assay, we quantitated the seeding activity of affected human brains. End-point assay using serially diluted brain homogenates of sporadic Creutzfeldt-Jakob disease patients demonstrated that 50% seeding dose (SD50 is reached approximately 10(10/g brain (values varies 10(8.79-10.63/g. A genetic case (GSS-P102L yielded a similar level of seeding activity in an autopsy brain sample. The range of PrPSc concentrations in the samples, determined by dot-blot assay, was 0.6-5.4 μg/g brain; therefore, we estimated that 1 SD50 unit was equivalent to 0.06-0.27 fg of PrPSc. The SD50 values of the affected brains dropped more than three orders of magnitude after autoclaving at 121°C. This new method for quantitation of human prion activity provides a new way to reduce the risk of iatrogenic prion transmission.

  17. Presence and seeding activity of pathological prion protein (PrP(TSE in skeletal muscles of white-tailed deer infected with chronic wasting disease.

    Directory of Open Access Journals (Sweden)

    Martin L Daus

    Full Text Available Chronic wasting disease (CWD is a contagious, rapidly spreading transmissible spongiform encephalopathy (TSE, or prion disease, occurring in cervids such as white tailed-deer (WTD, mule deer or elk in North America. Despite efficient horizontal transmission of CWD among cervids natural transmission of the disease to other species has not yet been observed. Here, we report for the first time a direct biochemical demonstration of pathological prion protein PrP(TSE and of PrP(TSE-associated seeding activity, the static and dynamic biochemical markers for biological prion infectivity, respectively, in skeletal muscles of CWD-infected cervids, i. e. WTD for which no clinical signs of CWD had been recognized. The presence of PrP(TSE was detected by Western- and postfixed frozen tissue blotting, while the seeding activity of PrP(TSE was revealed by protein misfolding cyclic amplification (PMCA. Semi-quantitative Western blotting indicated that the concentration of PrP(TSE in skeletal muscles of CWD-infected WTD was approximately 2000-10,000-fold lower than in brain tissue. Tissue-blot-analyses revealed that PrP(TSE was located in muscle-associated nerve fascicles but not, in detectable amounts, in myocytes. The presence and seeding activity of PrP(TSE in skeletal muscle from CWD-infected cervids suggests prevention of such tissue in the human diet as a precautionary measure for food safety, pending on further clarification of whether CWD may be transmissible to humans.

  18. De novo prions

    OpenAIRE

    Legname, Giuseppe; Geschwind, Michael; Benetti, Federico

    2010-01-01

    Prions are responsible for a heterogeneous group of fatal neurodegenerative diseases. They occur in three forms - sporadic, genetic, or acquired - and involve non-covalent post-translational modifications of the cellular prion protein (PrPC). Prions (PrPSc) are characterized by their infectious properties and intrinsic ability to act as a template, converting the normal, physiological PrPC into the pathological form, PrPSc. The ‘protein-only’ hypothesis, postulated by Stanley B Prusiner, impl...

  19. Sporadic Creutzfeldt-Jakob Disease: Prion Pathology in Medulla Oblongata—Possible Routes of Infection and Host Susceptibility

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    Diego Iacono

    2015-01-01

    Full Text Available Sporadic Creutzfeldt-Jakob disease (sCJD, the most frequent human prion disorder, is characterized by remarkable phenotypic variability, which is influenced by the conformation of the pathologic prion protein and the methionine/valine polymorphic codon 129 of the prion protein gene. While the etiology of sCJD remains unknown, it has been hypothesized that environmental exposure to prions might occur through conjunctival/mucosal contact, oral ingestion, inhalation, or simultaneous involvement of the olfactory and enteric systems. We studied 21 subjects with definite sCJD to assess neuropathological involvement of the dorsal motor nucleus of the vagus and other medullary nuclei and to evaluate possible associations with codon 129 genotype and prion protein conformation. The present data show that prion protein deposition was detected in medullary nuclei of distinct sCJD subtypes, either valine homozygous or heterozygous at codon 129. These findings suggest that an “environmental exposure” might occur, supporting the hypothesis that external sources of contamination could contribute to sCJD in susceptible hosts. Furthermore, these novel data could shed the light on possible causes of sCJD through a “triple match” hypothesis that identify environmental exposure, host genotype, and direct exposure of specific anatomical regions as possible pathogenetic factors.

  20. Is Parkinson’s Disease Truly a Prion-Like Disorder? An Appraisal of Current Evidence

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    Aneesha Chauhan

    2015-01-01

    Full Text Available Parkinson’s disease (PD is the world’s second most common neurodegenerative disease and most common movement disorder. Characterised by a loss of dopaminergic neurons and the development of intraneuronal inclusions known as Lewy bodies, it has classically been thought of as a cell-autonomous disease. However, in 2008, two groups reported the startling observation of Lewy bodies within embryonic neuronal grafts transplanted into PD patients little more than a decade previously, suggesting that PD pathology can be propagated to neighbouring cells and calling basic assumptions of our understanding of the disease into question. Subsequent research has largely served to confirm this interpretation, pointing towards a prion-like intercellular transfer of misfolded α-synuclein, the main component of Lewy bodies, as central to PD. This shift in thinking offers a revolutionary approach to PD treatment, potentially enabling a transition from purely symptomatic therapy to direct targeting of the pathology that drives disease progression. In this short review, we appraise current experimental support for PD as a prion-like disease, whilst highlighting areas of controversy or inconsistency which must be resolved. We also offer a brief discussion of the therapeutic implications of these discoveries.

  1. The presence of disease-associated prion protein in skeletal muscle of cattle infected with classical bovine spongiform encephalopathy.

    Science.gov (United States)

    Okada, Hiroyuki; Miyazawa, Kohtaro; Fukuda, Shigeo; Iwamaru, Yoshifumi; Imamura, Morikazu; Masujin, Kentaro; Matsuura, Yuichi; Fujii, Takashi; Fujii, Kei; Kageyama, Soichi; Yoshioka, Miyako; Murayama, Yuichi; Yokoyama, Takashi

    2014-01-01

    The aim of this study was to investigate the presence of disease-associated prion protein (PrP(Sc)) in the skeletal muscle of cattle infected with classical bovine spongiform encephalopathy (C-BSE). The study was carried out systematically in 12 different muscle samples from 43 (3 field and 40 experimental) cases of C-BSE; however, muscle spindles were not available in many of these cases. Therefore, analysis became restricted to a total of 31 muscles in 23 cattle. Even after this restriction, low levels of PrP(Sc) were detected in the muscle spindles of the masseter, intercostal, triceps brachii, psoas major, quadriceps femoris and semitendinosus muscles from 3 field and 6 experimental clinical-stage cases. The present data indicate that small amounts of PrP(Sc) are detectable by immunohistochemistry in the skeletal muscles of animals terminally affected with C-BSE.

  2. A BRIEF DISCUSSION REGARDING PRION DISEASES AND SARS

    Science.gov (United States)

    Recent diagnoses of Mad Cow disease in Canadian and American cattle has increased concern for this disease and other TSEs in North America. This presentation provides a quick review of the important features of Mad Cow disease as well as SARS as they might relate to land applicat...

  3. Lymphotoxin, but Not TNF, Is Required for Prion Invasion of Lymph Nodes

    OpenAIRE

    Tracy O'Connor; Nathalie Frei; Jana Sponarova; Petra Schwarz; Mathias Heikenwalder; Adriano Aguzzi

    2012-01-01

    Author Summary Prions are unique infectious agents thought to be composed entirely of an abnormal conformer of the endogenous prion protein. Prions cause a severe neurological disorder in humans and other animals known as prion disease. Though prion disease can arise spontaneously or from genetic mutations in the gene encoding the prion protein, many cases of prion disease arise due to peripheral exposure to the infectious agent. In these cases, prions must journey from the gastrointestinal t...

  4. Mad Cows and CJD A Physicist's View of Prion Brain Diseases

    CERN Document Server

    Morrison, Douglas Robert Ogston

    1997-01-01

    The research of Carleton Gajdusek on a stone-age tribe in Papua New Guinea, who suffered from a mysterious disease, kuru, spread by cannibalism, is described and short extracts from his films will be shown. Some deaths from kuru are still occuring after 45 years. This disease is believed to be caused by an entirely new mechanism, not a virus or bacteria, but by a small molecule known as a prion that occurs naturally in many living forms. The Prion Only hypothesis of Stan Prusiner is discussed critically. It has been calculated that 900,000 cows in Britain had the Mad Cow disease, BSE, but most were slaughtered before symptoms were recognised. This epidemic started with 10 cases in the first year, and finally 160,000 were officially classified as having BSE; it is now slowly dying out. The human epidemic, caused by a new version of Creutzfeldt-Jakob Disease, nvCJD, affects mainly young people, has just begun with 10 cases in the first year. The average incubation time may be about 14 years then death follows i...

  5. Inhibition of protease-resistant prion protein formation in a transformed deer cell line infected with chronic wasting disease

    NARCIS (Netherlands)

    Raymond, G.J.; Olsen, E.A.; Lee, K.S.; Raymond, L.D.; Bryant, P.K.; Baron, G.S.; Caughey, W.S.; Kocisko, D.A.; McHolland, L.E.; Favara, C.; Langeveld, J.P.M.; Zijderveld, van F.G.; Mayer, R.T.; Miller, M.W.; Williams, E.S.; Caughey, B.

    2006-01-01

    Chronic wasting disease (CWD) is an emerging transmissible spongiform encephalopathy (prion disease) of North American cervids, i.e., mule deer, white-tailed deer, and elk (wapiti). To facilitate in vitro studies of CWD, we have developed a transformed deer cell line that is persistently infected wi

  6. MM2-Thalamic Creutzfeldt-Jacob Disease: Neuropathological, Biochemical and Transmission Studies Identify a Distinctive Prion Strain

    NARCIS (Netherlands)

    Moda, F.; Suardi, S.; Fede, Di G.; Indaco, A.; Limido, L.; Vimercati, C.; Ruggerone, M.; Campagnani, I.; Langeveld, J.P.M.; Terruzzi, A.; Brambilla, A.; Zerbi, P.; Fociani, P.; Bishop, T.; Will, G.W.; Manson, J.C.; Giaccone, G.; Tagliavini, F.

    2012-01-01

    In CreutzfeldtJakob disease (CJD), molecular typing based on the size of the protease resistant core of the disease-associated prion protein (PrPSc) and the M/V polymorphism at codon 129 of the PRNP gene correlates with the clinico-pathologic subtypes. Approximately 95% of the sporadic 129MM CJD pat

  7. Transmission and Detection of Prions in Feces

    OpenAIRE

    Safar, Jiri G; Lessard, Pierre; Tamgüney, Gültekin; Freyman, Yevgeniy; Deering, Camille; Letessier, Frederic; Stephen J DeArmond; Prusiner, Stanley B.

    2008-01-01

    In chronic wasting disease (CWD) of cervids and scrapie of sheep, prions appear to be transmitted horizontally. Oral exposure to prion-tainted blood, urine, saliva and feces has been suggested as the mode of transmission for CWD and scrapie among herbivores susceptible to these prion diseases. To explore the transmission of prions through feces, uninoculated Syrian hamsters (SHa) were cohabitated with or exposed to the bedding of SHa orally infected with Sc237 prions. Incubation times of ~140...

  8. Prion病与睡眠障碍%Prion diseases and sleep disorders

    Institute of Scientific and Technical Information of China (English)

    詹淑琴; 郭彩凤; 王玉平; 贾建平

    2013-01-01

    Prion diseases (PrD) are a group of encephalopathies with neurodegenerative changes caused by prion protein (PrP) whose characteristic datum is transmissibility.In most cases they occur in a sporadic form although a group of them are familial associated with mutations in PrP gene.Phenotypic variability of fatal familial insomnia (FFI) versus familial Creutzfeldt-Jakob disease178 (fCJD178) seems to determine the different methionine-valine polymorphism at codon 129 of the PrP gene.Sleep disorders is one of the important clinical features for the diagnosis and definition of PrD.FFI,a hereditary disorder characterized by loss of physiological sleep with oneiric stupor,autonomic and motor hyperactivity.The polysomnography (PSG) shows disappearance of the physiological pattern of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep,as well as sleep spindles and K-complexes were absent.The hypothesis of the origin of these disorders is thalamic neuronal loss,especially in the anterior and dorsomedial nuclei,described in the neuropathology of these patients; besides,PET reveals hypofunction of thalamic nuclei,centres responsible for controlling wake-sleep.In CJD the wake-sleep disorders is not considered characteristic; nonetheless,frequent alterations have been found in the electroencephalographic registers of sleep.Besides thalamic neurodegeneration,there could be common etiopathogenic mechanisms in PrD in relation to the biological function of PrP.%Prion病是由传染性朊蛋白侵袭中枢神经系统引起的致死性神经变性脑病,睡眠障碍在Prion病中十分常见,也是其诊断特征之一.其中致死性家族性失眠症表现为严重的生理睡眠缺失及特殊梦幻状态、自主神经功能失调和过度运动;多导睡眠图早期睡眠纺锤波和K复合波消失,无法产生快速眼动和非快速眼动睡眠生理循环.除PET扫描呈现丘脑低代谢,神经病理学观察可见丘脑神经元大量缺失,尤其是丘脑

  9. [From the Scrapie syndrome of sheep and goat to the mad cow disease - the history of the discovery of prion].

    Science.gov (United States)

    Liu, Rui; Weng, Yi

    2009-05-01

    Since the discovery of Scrapie Syndrome in sheep and goats in 1730, there emerged a series of diseases such as Creutzfeldt-Jakob disease, kuru disease and mad cow disease etc. In the research of kuru disease, the American scientist D. Carlteton Gajdusek found a new virus without the characteristic of DNA and RNA, which was awarded the Nobel Prize in physiology in 1976. Since then another American scientist, Stanley B. Prusiner, found a new virus-prion, taking protein as the genetic medium, which was awarded the Nobel prize in physiology and medicine in 1997. The discovery of prion is a great landmark in the research of life science, which laid a theoretical foundation for people to conquer a series of diseases such as Scrapie syndrome in sheep and goats, Creutzfeldt-Jakob disease, kuru disease and mad cow disease etc. PMID:19930927

  10. Using Mass Spectrometry to Diagnose Prion diseases: Can we do that?

    Science.gov (United States)

    Prions (PrPSc) are infectious proteins. They are able to convert a normal cellular protein (PrPC) into a prion and, thereby, propagate an infection. We have used mass spectrometry to quantitate the prions present in infected hamsters, mice, and sheep. Calibration curves relating the area ratios of t...

  11. The many shades of prion strain adaptation.

    Science.gov (United States)

    Baskakov, Ilia V

    2014-01-01

    In several recent studies transmissible prion disease was induced in animals by inoculation with recombinant prion protein amyloid fibrils produced in vitro. Serial transmission of amyloid fibrils gave rise to a new class of prion strains of synthetic origin. Gradual transformation of disease phenotypes and PrP(Sc) properties was observed during serial transmission of synthetic prions, a process that resembled the phenomenon of prion strain adaptation. The current article discusses the remarkable parallels between phenomena of prion strain adaptation that accompanies cross-species transmission and the evolution of synthetic prions occurring within the same host. Two alternative mechanisms underlying prion strain adaptation and synthetic strain evolution are discussed. The current article highlights the complexity of the prion transmission barrier and strain adaptation and proposes that the phenomenon of prion adaptation is more common than previously thought.

  12. Prion propagation, toxicity and degradation.

    Science.gov (United States)

    Aguzzi, Adriano; Falsig, Jeppe

    2012-07-01

    Prion science has been on a rollercoaster for two decades. In the mid 1990s, the specter of mad cow disease (bovine spongiform encephalopathy, BSE) provoked an unprecedented public scare that was first precipitated by the realization that this animal prion disease could be transmitted to humans and then rekindled by the evidence that BSE-infected humans could pass on the infection through blood transfusions. Along with the gradual disappearance of BSE, the interest in prions has waned with the general public, funding agencies and prospective PhD students. In the past few years, however, a bewildering variety of diseases have been found to share features with prion infections, including cell-to-cell transmission. Here we review these developments and summarize those open questions that we currently deem most interesting in prion biology: how do prions damage their hosts, and how do hosts attempt to neutralize invading prions? PMID:22735515

  13. The Overview of Methods for Detecting Prion Disease%朊病毒检测方法综述

    Institute of Scientific and Technical Information of China (English)

    鲁云; 李滋薇; 杨利峰; 赵德明

    2011-01-01

    Prion diseases are transmissible neurodegenerative disorders affecting humans and various mammal animals. The infectious agent, prion,is composed by a misfolded form of the prion protein (PrPSc) that propagates in the absence of nucleic acid. Due to PrPSc mainly expressed in the brain and low expression in other organs, hence the most important objective in prion research is to find effective and accurate methods to detect the disease and prevent it. In this paper,we mainly described the established detecting methods for prions based on prion features and pathogenic characteristics, we hoped that could be helpful for people to understand this disease well and find effective way for the early diagnoses, as well as helpful for food safety and human health.%传染性海绵状脑病(transmissible spongiform encephalopathies,TSEs)是由朊病毒引起的人和多种哺乳动物以神经退行性变化为主要特征的一种慢性消耗性传染病,也称作朊病毒病;其是由体内正常细胞表面的PrPC转变成PrPSc蛋白所导致.但PrpSc主要在脑内表达,在其他组织表达量很低,因此快捷准确的诊断方法对于该病有重要意义.作者重点介绍以朊病毒的致病特点为依据建立的检测方法,便于对该疾病的早期诊断、预防以及食品安全检测提供帮助,保障畜牧业的有序发展以及人类的健康.

  14. Codon 129 polymorphism of prion protein gene in is not a risk factor for Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Jerusa Smid

    2013-07-01

    Full Text Available Interaction of prion protein and amyloid-b oligomers has been demonstrated recently. Homozygosity at prion protein gene (PRNP codon 129 is associated with higher risk for Creutzfeldt-Jakob disease. This polymorphism has been addressed as a possible risk factor in Alzheimer disease (AD. Objective To describe the association between codon 129 polymorphisms and AD. Methods We investigated the association of codon 129 polymorphism of PRNP in 99 AD patients and 111 controls, and the association between this polymorphism and cognitive performance. Other polymorphisms of PRNP and additive effect of apolipoprotein E gene (ApoE were evaluated. Results Codon 129 genotype distribution in AD 45.5% methionine (MM, 42.2% methionine valine (MV, 12.1% valine (VV; and 39.6% MM, 50.5% MV, 9.9% VV among controls (p>0.05. There were no differences of cognitive performance concerning codon 129. Stratification according to ApoE genotype did not reveal difference between groups. Conclusion Codon 129 polymorphism is not a risk factor for AD in Brazilian patients.

  15. Degradation of the disease-associated prion protein by a serine protease from lichens.

    Directory of Open Access Journals (Sweden)

    Christopher J Johnson

    Full Text Available The disease-associated prion protein (PrP(TSE, the probable etiological agent of the transmissible spongiform encephalopathies (TSEs, is resistant to degradation and can persist in the environment. Lichens, mutualistic symbioses containing fungi, algae, bacteria and occasionally cyanobacteria, are ubiquitous in the environment and have evolved unique biological activities allowing their survival in challenging ecological niches. We investigated PrP(TSE inactivation by lichens and found acetone extracts of three lichen species (Parmelia sulcata, Cladonia rangiferina and Lobaria pulmonaria have the ability to degrade prion protein (PrP from TSE-infected hamsters, mice and deer. Immunoblots measuring PrP levels and protein misfolding cyclic amplification indicated at least two logs of reductions in PrP(TSE. Degradative activity was not found in closely related lichen species or in algae or a cyanobacterium that inhabit lichens. Degradation was blocked by Pefabloc SC, a serine protease inhibitor, but not inhibitors of other proteases or enzymes. Additionally, we found that PrP levels in PrP(TSE-enriched preps or infected brain homogenates are also reduced following exposure to freshly-collected P. sulcata or an aqueous extract of the lichen. Our findings indicate that these lichen extracts efficiently degrade PrP(TSE and suggest that some lichens could have potential to inactivate TSE infectivity on the landscape or be a source for agents to degrade prions. Further work to clone and characterize the protease, assess its effect on TSE infectivity and determine which organism or organisms present in lichens produce or influence the protease activity is warranted.

  16. Degradation of the disease-associated prion protein by a serine protease from lichens.

    Science.gov (United States)

    Johnson, C.J.; Bennett, J.P.; Biro, S.M.; Duque-Velasquez, J. C.; Rodriguez, C.M.; Bessen, R.A.; Rocke, T.E.

    2011-01-01

    The disease-associated prion protein (PrPTSE), the probable etiological agent of the transmissible spongiform encephalopathies (TSEs), is resistant to degradation and can persist in the environment. Lichens, mutualistic symbioses containing fungi, algae, bacteria and occasionally cyanobacteria, are ubiquitous in the environment and have evolved unique biological activities allowing their survival in challenging ecological niches. We investigated PrPTSE inactivation by lichens and found acetone extracts of three lichen species (Parmelia sulcata, Cladonia rangiferina and Lobaria pulmonaria) have the ability to degrade prion protein (PrP) from TSE-infected hamsters, mice and deer. Immunoblots measuring PrP levels and protein misfolding cyclic amplification indicated at least two logs of reductions in PrPTSE. Degradative activity was not found in closely related lichen species or in algae or a cyanobacterium that inhabit lichens. Degradation was blocked by Pefabloc SC, a serine protease inhibitor, but not inhibitors of other proteases or enzymes. Additionally, we found that PrP levels in PrPTSE-enriched preps or infected brain homogenates are also reduced following exposure to freshly-collected P. sulcata or an aqueous extract of the lichen. Our findings indicate that these lichen extracts efficiently degrade PrPTSE and suggest that some lichens could have potential to inactivate TSE infectivity on the landscape or be a source for agents to degrade prions. Further work to clone and characterize the protease, assess its effect on TSE infectivity and determine which organism or organisms present in lichens produce or influence the protease activity is warranted.

  17. Prions, prion-like prionoids, and neurodegenerative disorders.

    Science.gov (United States)

    Verma, Ashok

    2016-01-01

    Prion diseases or transmissible spongiform encephalopathies are fatal neurodegenerative diseases characterized by the aggregation and deposition of the misfolded prion protein in the brain. α-synuclein (α-syn)-associated multiple system atrophy has been recently shown to be caused by a bona fide α-syn prion strain. Several other misfolded native proteins such as β-amyloid, tau and TDP-43 share some aspects of prions although none of them is shown to be transmissible in nature or in experimental animals. However, these prion-like "prionoids" are causal to a variety of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The remarkable recent discovery of at least two new α-syn prion strains and their transmissibility in transgenic mice and in vitro cell models raises a distinct question as to whether some specific strain of other prionoids could have the capability of disease transmission in a manner similar to prions. In this overview, we briefly describe human and other mammalian prion diseases and comment on certain similarities between prion and prionoid and the possibility of prion-like transmissibility of some prionoid strains. PMID:27293325

  18. Prions, prion-like prionoids, and neurodegenerative disordersVacancy

    Directory of Open Access Journals (Sweden)

    Ashok Verma

    2016-01-01

    Full Text Available Prion diseases or transmissible spongiform encephalopathies are fatal neurodegenerative diseases characterized by the aggregation and deposition of the misfolded prion protein in the brain. α-synuclein (α-syn-associated multiple system atrophy has been recently shown to be caused by a bona fide α-syn prion strain. Several other misfolded native proteins such as β-amyloid, tau and TDP-43 share some aspects of prions although none of them is shown to be transmissible in nature or in experimental animals. However, these prion-like “prionoids” are causal to a variety of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The remarkable recent discovery of at least two new α-syn prion strains and their transmissibility in transgenic mice and in vitro cell models raises a distinct question as to whether some specific strain of other prionoids could have the capability of disease transmission in a manner similar to prions. In this overview, we briefly describe human and other mammalian prion diseases and comment on certain similarities between prion and prionoid and the possibility of prion-like transmissibility of some prionoid strains.

  19. Prions, prion-like prionoids, and neurodegenerative disorders.

    Science.gov (United States)

    Verma, Ashok

    2016-01-01

    Prion diseases or transmissible spongiform encephalopathies are fatal neurodegenerative diseases characterized by the aggregation and deposition of the misfolded prion protein in the brain. α-synuclein (α-syn)-associated multiple system atrophy has been recently shown to be caused by a bona fide α-syn prion strain. Several other misfolded native proteins such as β-amyloid, tau and TDP-43 share some aspects of prions although none of them is shown to be transmissible in nature or in experimental animals. However, these prion-like "prionoids" are causal to a variety of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The remarkable recent discovery of at least two new α-syn prion strains and their transmissibility in transgenic mice and in vitro cell models raises a distinct question as to whether some specific strain of other prionoids could have the capability of disease transmission in a manner similar to prions. In this overview, we briefly describe human and other mammalian prion diseases and comment on certain similarities between prion and prionoid and the possibility of prion-like transmissibility of some prionoid strains.

  20. Comparison of Inflammatory and Acute-Phase Responses in the Brain and Peripheral Organs of the ME7 Model of Prion Disease

    OpenAIRE

    Cunningham, Colm; Wilcockson, David C.; Boche, Delphine; Perry, V. Hugh

    2005-01-01

    Chronic neurodegenerative diseases such as prion disease and Alzheimer's disease (AD) are reported to be associated with microglial activation and increased brain and serum cytokines and acute-phase proteins (APPs). Unlike AD, prion disease is also associated with a peripheral component in that the presumed causative agent, PrPSc, also accumulates in the spleen and other lymphoreticular organs. It is unclear whether the reported systemic acute-phase response represents a systemic inflammatory...

  1. Physiological and environmental control of yeast prions

    OpenAIRE

    Chernova, Tatiana A.; Wilkinson, Keith D.; Chernoff, Yury O.

    2013-01-01

    Prions are self-perpetuating protein isoforms that cause fatal and incurable neurodegenerative disease in mammals. Recent evidence indicates that a majority of human proteins involved in amyloid and neural inclusion disorders possess at least some prion properties. In lower eukaryotes, such as yeast, prions act as epigenetic elements, which increase phenotypic diversity by altering a range of cellular processes. While some yeast prions are clearly pathogenic, it is also postulated that prion ...

  2. Prions, protein homeostasis, and phenotypic diversity

    OpenAIRE

    Halfmann, Randal; Alberti, Simon; Lindquist, Susan

    2010-01-01

    Prions are fascinating but often misunderstood protein aggregation phenomena. The traditional association of the mammalian prion protein with disease has overshadowed a potentially more interesting attribute of prions: their ability to create protein-based molecular memories. In fungi, prions alter the relationship between genotype and phenotype in a heritable way that diversifies clonal populations. Recent findings in yeast indicate that prions might be much more common than previously real...

  3. Grass plants bind, retain, uptake and transport infectious prions

    OpenAIRE

    Sandra Pritzkow; Rodrigo Morales; Fabio Moda; Uffaf Khan; Glenn C. Telling; Edward Hoover; Claudio Soto

    2015-01-01

    Prions are the protein-based infectious agents responsible for prion diseases. Environmental prion contamination has been implicated in disease transmission. Here, we analyzed the binding and retention of infectious prion protein (PrPSc) to plants. Small quantities of PrPSc contained in diluted brain homogenate or in excretory materials (urine and feces) can bind to wheat grass roots and leaves. Wild-type hamsters were efficiently infected by ingestion of prion-contaminated plants. The prion-...

  4. Recent progress in prion and prion-like protein aggregation

    Institute of Scientific and Technical Information of China (English)

    Chuan-Wei Yi; Wen-Chang Xu; Jie Chen; Yi Liang

    2013-01-01

    Prion diseases and prion-like protein misfolding diseases involve the accumulation of abnormally aggregated forms of the normal host proteins,such as prion protein and Tau protein.These proteins are special because of their self-duplicating and transmissible characteristics.Such abnormally aggregated proteins mainly formed in neurons,cause the neurons dysfunction,and finally lead to invariably fatal neurodegenerative diseases.Prion diseases appear not only in animals,such as bovine spongiform encephalopathy in cattle and scrapie in sheep,but also in humans,such as Creutzfeldt-Jacob disease,and even the same prion or prion-like proteins can have many different phenotypes.A lot of biological evidence has suggested that the molecular basis for different strains of prions could be hidden in protein conformations,and the misfolded proteins with conformations different from the normal proteins have been proved to be the main cause for protein aggregation.Crowded physiological environments can be imitated in vitro to study how the misfolding of these proteins leads to the diseases in vivo.In this review,we provide an overview of the existing structural information for prion and prion-like proteins,and discuss the post-translational modifications of prion proteins and the difference between prion and other infectious pathogens.We also discuss what makes a misfolded protein become an infectious agent,and show some examples of prion-like protein aggregation,such as Tau protein aggregation and superoxide dismutase 1 aggregation,as well as some cases of prion-like protein aggregation in crowded physiological environments.

  5. PrionHome: a database of prions and other sequences relevant to prion phenomena.

    Directory of Open Access Journals (Sweden)

    Djamel Harbi

    Full Text Available Prions are units of propagation of an altered state of a protein or proteins; prions can propagate from organism to organism, through cooption of other protein copies. Prions contain no necessary nucleic acids, and are important both as both pathogenic agents, and as a potential force in epigenetic phenomena. The original prions were derived from a misfolded form of the mammalian Prion Protein PrP. Infection by these prions causes neurodegenerative diseases. Other prions cause non-Mendelian inheritance in budding yeast, and sometimes act as diseases of yeast. We report the bioinformatic construction of the PrionHome, a database of >2000 prion-related sequences. The data was collated from various public and private resources and filtered for redundancy. The data was then processed according to a transparent classification system of prionogenic sequences (i.e., sequences that can make prions, prionoids (i.e., proteins that propagate like prions between individual cells, and other prion-related phenomena. There are eight PrionHome classifications for sequences. The first four classifications are derived from experimental observations: prionogenic sequences, prionoids, other prion-related phenomena, and prion interactors. The second four classifications are derived from sequence analysis: orthologs, paralogs, pseudogenes, and candidate-prionogenic sequences. Database entries list: supporting information for PrionHome classifications, prion-determinant areas (where relevant, and disordered and compositionally-biased regions. Also included are literature references for the PrionHome classifications, transcripts and genomic coordinates, and structural data (including comparative models made for the PrionHome from manually curated alignments. We provide database usage examples for both vertebrate and fungal prion contexts. Using the database data, we have performed a detailed analysis of the compositional biases in known budding-yeast prionogenic

  6. Brain region specific pre-synaptic and post-synaptic degeneration are early components of neuropathology in prion disease.

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    Zuzana Šišková

    Full Text Available Synaptic abnormalities, one of the key features of prion disease pathogenesis, gives rise to functional deficits and contributes to the devastating clinical outcome. The synaptic compartment is the first to succumb in several neurodegenerative diseases linked with protein misfolding but the mechanisms underpinning this are poorly defined. In our current study we document that a focal intrahippocampal injection of the mouse-adapted 22L scrapie strain produces a complex, region-specific pathology in the brain. Our findings reveal that early synaptic changes in the stratum radiatum of the hippocampus, identical to those observed with the ME7 strain, occur when 22L strain is introduced into the hippocampus. The pathology was defined by degenerating Type I pre-synaptic elements progressively enveloped by the post-synaptic density of the dendritic spine. In contrast, the pathology in the cerebellum suggested that dendritic disintegration rather than pre-synaptic abnormalities dominate the early degenerative changes associated with the Purkinje cells. Indeed, both of the major synaptic inputs into the cerebellum, which arise from the parallel and climbing fibers, remained intact even at late stage disease. Immunolabeling with pathway selective antibodies reinforced these findings. These observations demonstrate that neuronal vulnerability to pathological protein misfolding is strongly dependent on the structure and function of the target neurons.

  7. Distinct transmissibility features of TSE sources derived from ruminant prion diseases by the oral route in a transgenic mouse model (TgOvPrP4 overexpressing the ovine prion protein.

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    Jean-Noël Arsac

    Full Text Available Transmissible spongiform encephalopathies (TSEs are a group of fatal neurodegenerative diseases associated with a misfolded form of host-encoded prion protein (PrP. Some of them, such as classical bovine spongiform encephalopathy in cattle (BSE, transmissible mink encephalopathy (TME, kuru and variant Creutzfeldt-Jakob disease in humans, are acquired by the oral route exposure to infected tissues. We investigated the possible transmission by the oral route of a panel of strains derived from ruminant prion diseases in a transgenic mouse model (TgOvPrP4 overexpressing the ovine prion protein (A136R154Q171 under the control of the neuron-specific enolase promoter. Sources derived from Nor98, CH1641 or 87V scrapie sources, as well as sources derived from L-type BSE or cattle-passaged TME, failed to transmit by the oral route, whereas those derived from classical BSE and classical scrapie were successfully transmitted. Apart from a possible effect of passage history of the TSE agent in the inocula, this implied the occurrence of subtle molecular changes in the protease-resistant prion protein (PrPres following oral transmission that can raises concerns about our ability to correctly identify sheep that might be orally infected by the BSE agent in the field. Our results provide proof of principle that transgenic mouse models can be used to examine the transmissibility of TSE agents by the oral route, providing novel insights regarding the pathogenesis of prion diseases.

  8. Prion protein polymorphisms in white-tailed deer influence susceptibility to chronic wasting disease.

    Science.gov (United States)

    Johnson, Chad; Johnson, Jody; Vanderloo, Joshua P; Keane, Delwyn; Aiken, Judd M; McKenzie, Debbie

    2006-07-01

    The primary sequence of the prion protein affects susceptibility to transmissible spongiform encephalopathies, or prion diseases, in mice, sheep and humans. The Prnp gene sequence of free-ranging, Wisconsin white-tailed deer was determined and the Prnp genotypes of chronic wasting disease (CWD)-positive and CWD-negative deer were compared. Six amino acid changes were identified, two of which were located in pseudogenes. Two alleles, a Q-->K polymorphism at codon 226 and a single octapeptide repeat insertion into the pseudogene, have not been reported previously. The predominant alleles--wild-type (Q95, G96 and Q226) and a G96S polymorphism--comprised almost 98% of the Prnp alleles in the Wisconsin white-tailed deer population. Comparison of the allelic frequencies in the CWD-positive and CWD-negative deer suggested that G96S and a Q95H polymorphism were linked to a reduced susceptibility to CWD. The G96S allele did not, however, provide complete resistance, as a CWD-positive G96S/G96S deer was identified. The G96S allele was also linked to slower progression of the disease in CWD-positive deer based on the deposition of PrP(CWD) in the obex region of the medulla oblongata. Although the reduced susceptibility of deer with at least one copy of the Q95H or G96S allele is insufficient to serve as a genetic barrier, the presence of these alleles may modulate the impact of CWD on white-tailed deer populations.

  9. Controlling the prion propensity of glutamine/asparagine-rich proteins.

    Science.gov (United States)

    Paul, Kacy R; Ross, Eric D

    2015-01-01

    The yeast Saccharomyces cerevisiae can harbor a number of distinct prions. Most of the yeast prion proteins contain a glutamine/asparagine (Q/N) rich region that drives prion formation. Prion-like domains, defined as regions with high compositional similarity to yeast prion domains, are common in eukaryotic proteomes, and mutations in various human proteins containing prion-like domains have been linked to degenerative diseases, including amyotrophic lateral sclerosis. Here, we discuss a recent study in which we utilized two strategies to generate prion activity in non-prion Q/N-rich domains. First, we made targeted mutations in four non-prion Q/N-rich domains, replacing predicted prion-inhibiting amino acids with prion-promoting amino acids. All four mutants formed foci when expressed in yeast, and two acquired bona fide prion activity. Prion activity could be generated with as few as two mutations, suggesting that many non-prion Q/N-rich proteins may be just a small number of mutations from acquiring aggregation or prion activity. Second, we created tandem repeats of short prion-prone segments, and observed length-dependent prion activity. These studies demonstrate the considerable progress that has been made in understanding the sequence basis for aggregation of prion and prion-like domains, and suggest possible mechanisms by which new prion domains could evolve.

  10. Prions in skeletal muscle

    OpenAIRE

    Patrick J Bosque; Ryou, Chongsuk; Telling, Glenn; Peretz, David; Legname, Giuseppe; Stephen J DeArmond; Prusiner, Stanley B.

    2002-01-01

    Considerable evidence argues that consumption of beef products from cattle infected with bovine spongiform encephalopathy (BSE) prions causes new variant Creutzfeldt–Jakob disease. In an effort to prevent new variant Creutzfeldt–Jakob disease, certain “specified offals,” including neural and lymphatic tissues, thought to contain high titers of prions have been excluded from foods destined for human consumption [Phillips, N. A., Bridgeman, J. & Ferguson-Smith, M. (2000) in The BSE Inquiry (Sta...

  11. Abnormal isoform of prion protein accumulates in follicular dendritic cells in mice with Creutzfeldt-Jakob disease.

    OpenAIRE

    Kitamoto, T.; Muramoto, T; Mohri, S; DOH-URA, K; Tateishi, J.

    1991-01-01

    We established that follicular dendritic cells (FDCs) are the site of abnormal prion protein (PrPCJD) accumulations in lymphoid tissues from mice infected with Creutzfeldt-Jakob disease. Evidence of positive FDC staining was observed in Creutzfeldt-Jakob disease-infected mice irrespective of the inoculation route, while no such staining was seen in the control mice. We also found that the severe combined immunodeficiency mouse trait is transmittable via the intracranial route but not via the ...

  12. Prion protein gene sequence and chronic wasting disease susceptibility in white-tailed deer (Odocoileus virginianus).

    Science.gov (United States)

    Brandt, Adam L; Kelly, Amy C; Green, Michelle L; Shelton, Paul; Novakofski, Jan; Mateus-Pinilla, Nohra E

    2015-01-01

    The sequence of the prion protein gene (PRNP) affects susceptibility to spongiform encephalopathies, or prion diseases in many species. In white-tailed deer, both coding and non-coding single nucleotide polymorphisms have been identified in this gene that correlate to chronic wasting disease (CWD) susceptibility. Previous studies examined individual nucleotide or amino acid mutations; here we examine all nucleotide polymorphisms and their combined effects on CWD. A 626 bp region of PRNP was examined from 703 free-ranging white-tailed deer. Deer were sampled between 2002 and 2010 by hunter harvest or government culling in Illinois and Wisconsin. Fourteen variable nucleotide positions were identified (4 new and 10 previously reported). We identified 68 diplotypes comprised of 24 predicted haplotypes, with the most common diplotype occurring in 123 individuals. Diplotypes that were found exclusively among positive or negative animals were rare, each occurring in less than 1% of the deer studied. Only one haplotype (C, odds ratio 0.240) and 2 diplotypes (AC and BC, odds ratios of 0.161 and 0.108 respectively) has significant associations with CWD resistance. Each contains mutations (one synonymous nucleotide 555C/T and one nonsynonymous nucleotide 286G/A) at positions reported to be significantly associated with reduced CWD susceptibility. Results suggest that deer populations with higher frequencies of haplotype C or diplotypes AC and BC might have a reduced risk for CWD infection--while populations with lower frequencies may have higher risk for infection. Understanding the genetic basis of CWD has improved our ability to assess herd susceptibility and direct management efforts within CWD infected areas.

  13. Prion protein gene sequence and chronic wasting disease susceptibility in white-tailed deer (Odocoileus virginianus).

    Science.gov (United States)

    Brandt, Adam L; Kelly, Amy C; Green, Michelle L; Shelton, Paul; Novakofski, Jan; Mateus-Pinilla, Nohra E

    2015-01-01

    The sequence of the prion protein gene (PRNP) affects susceptibility to spongiform encephalopathies, or prion diseases in many species. In white-tailed deer, both coding and non-coding single nucleotide polymorphisms have been identified in this gene that correlate to chronic wasting disease (CWD) susceptibility. Previous studies examined individual nucleotide or amino acid mutations; here we examine all nucleotide polymorphisms and their combined effects on CWD. A 626 bp region of PRNP was examined from 703 free-ranging white-tailed deer. Deer were sampled between 2002 and 2010 by hunter harvest or government culling in Illinois and Wisconsin. Fourteen variable nucleotide positions were identified (4 new and 10 previously reported). We identified 68 diplotypes comprised of 24 predicted haplotypes, with the most common diplotype occurring in 123 individuals. Diplotypes that were found exclusively among positive or negative animals were rare, each occurring in less than 1% of the deer studied. Only one haplotype (C, odds ratio 0.240) and 2 diplotypes (AC and BC, odds ratios of 0.161 and 0.108 respectively) has significant associations with CWD resistance. Each contains mutations (one synonymous nucleotide 555C/T and one nonsynonymous nucleotide 286G/A) at positions reported to be significantly associated with reduced CWD susceptibility. Results suggest that deer populations with higher frequencies of haplotype C or diplotypes AC and BC might have a reduced risk for CWD infection--while populations with lower frequencies may have higher risk for infection. Understanding the genetic basis of CWD has improved our ability to assess herd susceptibility and direct management efforts within CWD infected areas. PMID:26634768

  14. Role of Prion Replication in the Strain-dependent Brain Regional Distribution of Prions.

    Science.gov (United States)

    Hu, Ping Ping; Morales, Rodrigo; Duran-Aniotz, Claudia; Moreno-Gonzalez, Ines; Khan, Uffaf; Soto, Claudio

    2016-06-10

    One intriguing feature of prion diseases is their strain variation. Prion strains are differentiated by the clinical consequences they generate in the host, their biochemical properties, and their potential to infect other animal species. The selective targeting of these agents to specific brain structures have been extensively used to characterize prion strains. However, the molecular basis dictating strain-specific neurotropism are still elusive. In this study, isolated brain structures from animals infected with four hamster prion strains (HY, DY, 139H, and SSLOW) were analyzed for their content of protease-resistant PrP(Sc) Our data show that these strains have different profiles of PrP deposition along the brain. These patterns of accumulation, which were independent of regional PrP(C) production, were not reproduced by in vitro replication when different brain regions were used as substrate for the misfolding-amplification reaction. On the contrary, our results show that in vitro replication efficiency depended exclusively on the amount of PrP(C) present in each part of the brain. Our results suggest that the variable regional distribution of PrP(Sc) in distinct strains is not determined by differences on prion formation, but on other factors or cellular pathways. Our findings may contribute to understand the molecular mechanisms of prion pathogenesis and strain diversity.

  15. Role of Prion Replication in the Strain-dependent Brain Regional Distribution of Prions.

    Science.gov (United States)

    Hu, Ping Ping; Morales, Rodrigo; Duran-Aniotz, Claudia; Moreno-Gonzalez, Ines; Khan, Uffaf; Soto, Claudio

    2016-06-10

    One intriguing feature of prion diseases is their strain variation. Prion strains are differentiated by the clinical consequences they generate in the host, their biochemical properties, and their potential to infect other animal species. The selective targeting of these agents to specific brain structures have been extensively used to characterize prion strains. However, the molecular basis dictating strain-specific neurotropism are still elusive. In this study, isolated brain structures from animals infected with four hamster prion strains (HY, DY, 139H, and SSLOW) were analyzed for their content of protease-resistant PrP(Sc) Our data show that these strains have different profiles of PrP deposition along the brain. These patterns of accumulation, which were independent of regional PrP(C) production, were not reproduced by in vitro replication when different brain regions were used as substrate for the misfolding-amplification reaction. On the contrary, our results show that in vitro replication efficiency depended exclusively on the amount of PrP(C) present in each part of the brain. Our results suggest that the variable regional distribution of PrP(Sc) in distinct strains is not determined by differences on prion formation, but on other factors or cellular pathways. Our findings may contribute to understand the molecular mechanisms of prion pathogenesis and strain diversity. PMID:27056328

  16. Controlling the prion propensity of glutamine/asparagine-rich proteins

    OpenAIRE

    Paul, Kacy R.; Ross, Eric D.

    2015-01-01

    ABSTRACT The yeast Saccharomyces cerevisiae can harbor a number of distinct prions. Most of the yeast prion proteins contain a glutamine/asparagine (Q/N) rich region that drives prion formation. Prion-like domains, defined as regions with high compositional similarity to yeast prion domains, are common in eukaryotic proteomes, and mutations in various human proteins containing prion-like domains have been linked to degenerative diseases, including amyotrophic lateral sclerosis. Here, we discu...

  17. MicroRNAs as a molecular basis for mental retardation, Alzheimer's and prion diseases.

    Science.gov (United States)

    Provost, Patrick

    2010-06-18

    MicroRNAs (miRNAs) are small, approximately 21- to 23-nucleotide (nt) non-coding RNA species that act as key regulators of gene expression along a central and well-defined cellular process known as RNA silencing, and involving the recognition and translational control of specific messenger RNA (mRNAs). Generated through the well-orchestrated and sequential processing of miRNA precursor molecules, mature miRNAs are subsequently incorporated into miRNA-containing ribonucleoprotein effector complexes to regulate mRNA translation through the recognition of specific binding sites of imperfect complementarity located mainly in the 3' untranslated region. Predicted to regulate up to 90% of the genes in humans, miRNAs may thus control cellular processes in all cells and tissues of the human body. Likely to play a central role in health and disease, a dysfunctional miRNA-based regulation of gene expression may represent the main etiologic factor underlying diseases affecting major organs, such as the brain. In this review article, the molecular mechanisms underlying the role and function of miRNAs in the regulation of genes involved in neurological and neurodegenerative diseases will be discussed, with a focus on the fragile X syndrome, Alzheimer's disease (AD) and prion disease.

  18. Research on Prion and Disease Caused by Prion%朊病毒概述及其所致疾病研究

    Institute of Scientific and Technical Information of China (English)

    李忠秋; 王君伟; 刘春龙

    2004-01-01

    Pmsiner提出了大分子蛋白质与感染性有关的假说,认为朊病毒是一种不含核酸、有部分蛋白酶抗性、具有感染性的蛋白粒子,且为了与病毒和类病毒(Viroids)相区分,用了朊病毒(Prion)这个概念。近几十年来,由于疯牛病(mad coW disease)导致了全世界的恐慌,特别是随着疯牛病的全球范围流行,由同一致病因子引起的人的变异型克雅氏症(new variant Creu.

  19. Prion sequence polymorphisms and chronic wasting disease resistance in Illinois white-tailed deer (Odocoileus virginianus).

    Science.gov (United States)

    Kelly, Amy C; Mateus-Pinilla, Nohra E; Diffendorfer, Jay; Jewell, Emily; Ruiz, Marilyn O; Killefer, John; Shelton, Paul; Beissel, Tom; Novakofski, Jan

    2008-01-01

    Nucleic acid sequences of the prion gene (PRNP) were examined and genotypes compiled for 76 white-tailed deer from northern Illinois, which previously tested positive for chronic wasting disease (CWD), and 120 negative animals selected to control for geographic location and age. Nine nucleotide polymorphisms, seven silent and two coding, were found in the sampled population. All observed polymorphisms except two of very low frequency were observed in both negative and positive animals, although five polymorphic loci had significantly different distributions of alleles between infected and non-infected individuals. Nucleotide base changes 60C/T, 285A/C, 286G/A and 555C/T were observed with higher than expected frequencies in CWD negative animals suggesting disease resistance, while 153C/T was observed more than expected in positive animals, suggesting susceptibility. The two coding polymorphisms, 285A/C (Q95H) and 286G/A (G96S), have been described in white-tailed deer populations sampled in Colorado and Wisconsin. Frequency distributions of coding polymorphisms in Wisconsin and Illinois deer populations were different, an unexpected result considering the sampled areas are less than 150 km apart. The total number of polymorphisms per animal, silent or coding, was negatively correlated to disease status. The potential importance of silent polymorphisms (60C/T, 153C/T, 555C/T), either individually or cumulatively, in CWD disease status has not been previously reported.

  20. Salivary prions in sheep and deer

    OpenAIRE

    Tamgüney, Gültekin; Richt, Jürgen A; Hamir, Amir N.; Greenlee, Justin J.; Miller, Michael W.; Wolfe, Lisa L; Sirochman, Tracey M; Young, Alan J; Glidden, David V.; Johnson, Natrina L.; Giles, Kurt; Stephen J DeArmond; Prusiner, Stanley B.

    2012-01-01

    Scrapie of sheep and chronic wasting disease (CWD) of cervids are transmissible prion diseases. Milk and placenta have been identified as sources of scrapie prions but do not explain horizontal transmission. In contrast, CWD prions have been reported in saliva, urine and feces, which are thought to be responsible for horizontal transmission. While the titers of CWD prions have been measured in feces, levels in saliva or urine are unknown. Because sheep produce ∼17 L/day of saliva and scrapie ...

  1. Mutation and polymorphism of the prion protein gene in Libyan Jews with Creutzfeldt-Jakob disease (CJD)

    Energy Technology Data Exchange (ETDEWEB)

    Gabizon, R.; Rosenmann, H.; Meiner, Z.; Kahana, I. (Hadassah Univ., Jerusalem (Israel)); Kahana, E. (Barzilai Medical Center, Ashkelon (Israel)); Shugart, Y.; Ott, J. (Columbia Univ., New York, NY (United States)); Prusiner, S.B. (Univ. of California, San Francisco, CA (United States))

    1993-10-01

    The inherited prion diseases are neurodegenerative disorders which are not only genetic but also transmissible. More than a dozen mutations in the prion protein gene that result in nonconservative amino acid substitutions segregate with the inherited prion diseases including familial Creutzfeldt-Jakob disease (CJD). In Israel, the incidence of CJD is about 1 case/10[sup 4] Libyan Jews. A Lys[sub 200] substitution segregates with CJD and is reported here to be genetically linked to CJD with a lod score of >4.8. Some healthy elderly Lys[sub 200] carriers > age 65 years were identified, suggesting the possibility of incomplete penetrance. In contrast, no linkage was found between the development of familial CJD and a polymorphism encoding either Met[sub 129] or Val[sub 129]. All Libyan Jewish CJD patients with the Lys[sub 200] mutation encode a Met[sub 129] on the mutant allele. Homozygosity for Met[sub 129] did not correlate with age at disease onset or the duration of illness. The frequency of the Met[sub 129] allele was higher in the affected pedigrees than in a control population of Libyan Jews. The frequency of the Met[sub 129] and Val[sub 129] alleles in the control Libyan population was similar to that found in the general Caucasian population. The identification of three Libyan Jews homozygous for the Lys[sub 200] mutation suggests frequent intrafamilial marriages, a custom documented by genealogical investigations. 26 refs., 3 figs., 6 tabs.

  2. Evidence for varied aetiologies regulating the transmission of prion disease: implications for understanding the heritable basis of prion incubation times.

    Directory of Open Access Journals (Sweden)

    Conrad O Iyegbe

    Full Text Available BACKGROUND: Transmissible Spongiform Encephalopathies (TSEs are a group of progressive fatal neurodegenerative disorders, triggered by abnormal folding of the endogenous prion protein molecule. The encoding gene is a major biological factor influencing the length of the asymptomatic period after infection. It remains unclear the extent to which the variation between quantitative trait loci (QTLs reported in mouse models is due to methodological differences between approaches or genuine differences between traits. With this in mind, our approach to identifying genetic factors has sought to extend the linkage mapping approach traditionally applied, to a series of additional traits, while minimising methodological variability between them. Our approach allows estimations of heritability to be derived, as well as predictions to be made about possible existence of genetic overlap between the various traits. METHODOLOGY/PRINCIPAL FINDINGS: Our data indicate a surprising degree of heritability (up to 60%. Correlations between traits are also identified. A series of QTLs on chromosomes 1, 2, 3, 4, 6, 11 and 18 accompany our heritability estimates. However, only a locus on chromosome 11 has a general effect across all 4 models explored. CONCLUSIONS/SIGNIFICANCE: We have achieved some success in detecting novel and pre-existing QTLs associated with incubation time. However, aside from the general effects described, the model-specific nature of the broader host genetic architecture has also been brought into clearer focus. This suggests that genetic overlap can only partially account for the general heritability of incubation time when factors, such as the nature of the TSE agent and the route of administration are considered. This point is highly relevant to vCJD (a potential threat to public health where the route of primary importance is oral, while the QTLs being sought derive exclusively from studies of the ic route. Our results highlight the

  3. Prions are affected by evolution at two levels.

    Science.gov (United States)

    Wickner, Reed B; Kelly, Amy C

    2016-03-01

    Prions, infectious proteins, can transmit diseases or be the basis of heritable traits (or both), mostly based on amyloid forms of the prion protein. A single protein sequence can be the basis for many prion strains/variants, with different biological properties based on different amyloid conformations, each rather stably propagating. Prions are unique in that evolution and selection work at both the level of the chromosomal gene encoding the protein, and on the prion itself selecting prion variants. Here, we summarize what is known about the evolution of prion proteins, both the genes and the prions themselves. We contrast the one known functional prion, [Het-s] of Podospora anserina, with the known disease prions, the yeast prions [PSI+] and [URE3] and the transmissible spongiform encephalopathies of mammals. PMID:26713322

  4. Prions are affected by evolution at two levels.

    Science.gov (United States)

    Wickner, Reed B; Kelly, Amy C

    2016-03-01

    Prions, infectious proteins, can transmit diseases or be the basis of heritable traits (or both), mostly based on amyloid forms of the prion protein. A single protein sequence can be the basis for many prion strains/variants, with different biological properties based on different amyloid conformations, each rather stably propagating. Prions are unique in that evolution and selection work at both the level of the chromosomal gene encoding the protein, and on the prion itself selecting prion variants. Here, we summarize what is known about the evolution of prion proteins, both the genes and the prions themselves. We contrast the one known functional prion, [Het-s] of Podospora anserina, with the known disease prions, the yeast prions [PSI+] and [URE3] and the transmissible spongiform encephalopathies of mammals.

  5. Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis-like disease.

    Science.gov (United States)

    Bidhendi, Elaheh Ekhtiari; Bergh, Johan; Zetterström, Per; Andersen, Peter M; Marklund, Stefan L; Brännström, Thomas

    2016-06-01

    Amyotrophic lateral sclerosis (ALS) is an adult-onset degeneration of motor neurons that is commonly caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Both patients and Tg mice expressing mutant human SOD1 (hSOD1) develop aggregates of unknown importance. In Tg mice, 2 different strains of hSOD1 aggregates (denoted A and B) can arise; however, the role of these aggregates in disease pathogenesis has not been fully characterized. Here, minute amounts of strain A and B hSOD1 aggregate seeds that were prepared by centrifugation through a density cushion were inoculated into lumbar spinal cords of 100-day-old mice carrying a human SOD1 Tg. Mice seeded with A or B aggregates developed premature signs of ALS and became terminally ill after approximately 100 days, which is 200 days earlier than for mice that had not been inoculated or were given a control preparation. Concomitantly, exponentially growing strain A and B hSOD1 aggregations propagated rostrally throughout the spinal cord and brainstem. The phenotypes provoked by the A and B strains differed regarding progression rates, distribution, end-stage aggregate levels, and histopathology. Together, our data indicate that the aggregate strains are prions that transmit a templated, spreading aggregation of hSOD1, resulting in a fatal ALS-like disease. PMID:27140399

  6. Genes contributing to prion pathogenesis

    DEFF Research Database (Denmark)

    Tamgüney, Gültekin; Giles, Kurt; Glidden, David V;

    2008-01-01

    incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in which the gene product was inactivated, knocked out or overexpressed. We tested 20 candidate genes...... show that many genes previously implicated in prion replication have no discernible effect on the pathogenesis of prion disease. While most genes tested did not significantly affect survival times, ablation of the amyloid beta (A4) precursor protein (App) or interleukin-1 receptor, type I (Il1r1...

  7. B cells and platelets harbor prion infectivity in the blood of deer infected with chronic wasting disease.

    Science.gov (United States)

    Mathiason, Candace K; Hayes-Klug, Jeanette; Hays, Sheila A; Powers, Jenny; Osborn, David A; Dahmes, Sallie J; Miller, Karl V; Warren, Robert J; Mason, Gary L; Telling, Glenn C; Young, Alan J; Hoover, Edward A

    2010-05-01

    Substantial evidence for prion transmission via blood transfusion exists for many transmissible spongiform encephalopathy (TSE) diseases. Determining which cell phenotype(s) is responsible for trafficking infectivity has important implications for our understanding of the dissemination of prions, as well as their detection and elimination from blood products. We used bioassay studies of native white-tailed deer and transgenic cervidized mice to determine (i) if chronic wasting disease (CWD) blood infectivity is associated with the cellular versus the cell-free/plasma fraction of blood and (ii) in particular if B-cell (MAb 2-104(+)), platelet (CD41/61(+)), or CD14(+) monocyte blood cell phenotypes harbor infectious prions. All four deer transfused with the blood mononuclear cell fraction from CWD(+) donor deer became PrP(CWD) positive by 19 months postinoculation, whereas none of the four deer inoculated with cell-free plasma from the same source developed prion infection. All four of the deer injected with B cells and three of four deer receiving platelets from CWD(+) donor deer became PrP(CWD) positive in as little as 6 months postinoculation, whereas none of the four deer receiving blood CD14(+) monocytes developed evidence of CWD infection (immunohistochemistry and Western blot analysis) after 19 months of observation. Results of the Tg(CerPrP) mouse bioassays mirrored those of the native cervid host. These results indicate that CWD blood infectivity is cell associated and suggest a significant role for B cells and platelets in trafficking CWD infectivity in vivo and support earlier tissue-based studies associating putative follicular B cells with PrP(CWD). Localization of CWD infectivity with leukocyte subpopulations may aid in enhancing the sensitivity of blood-based diagnostic assays for CWD and other TSEs. PMID:20219916

  8. Comparison of 2 synthetically generated recombinant prions

    OpenAIRE

    Zhang, Yi; Wang, Fei; Wang, Xinhe; Zhang, Zhihong; Xu, Yuanyuan; Yu, Guohua; Yuan, Chonggang; Ma, Jiyan

    2014-01-01

    Prion is a protein-conformation-based infectious agent causing fatal neurodegenerative diseases in humans and animals. Our previous studies revealed that in the presence of cofactors, infectious prions can be synthetically generated in vitro with bacterially expressed recombinant prion protein (PrP). Once initiated, the recombinant prion is able to propagate indefinitely via serial protein misfolding cyclic amplification (sPMCA). In this study, we compared 2 separately initiated recombinant p...

  9. Prion Amplification and Hierarchical Bayesian Modeling Refine Detection of Prion Infection

    Science.gov (United States)

    Wyckoff, A. Christy; Galloway, Nathan; Meyerett-Reid, Crystal; Powers, Jenny; Spraker, Terry; Monello, Ryan J.; Pulford, Bruce; Wild, Margaret; Antolin, Michael; Vercauteren, Kurt; Zabel, Mark

    2015-02-01

    Prions are unique infectious agents that replicate without a genome and cause neurodegenerative diseases that include chronic wasting disease (CWD) of cervids. Immunohistochemistry (IHC) is currently considered the gold standard for diagnosis of a prion infection but may be insensitive to early or sub-clinical CWD that are important to understanding CWD transmission and ecology. We assessed the potential of serial protein misfolding cyclic amplification (sPMCA) to improve detection of CWD prior to the onset of clinical signs. We analyzed tissue samples from free-ranging Rocky Mountain elk (Cervus elaphus nelsoni) and used hierarchical Bayesian analysis to estimate the specificity and sensitivity of IHC and sPMCA conditional on simultaneously estimated disease states. Sensitivity estimates were higher for sPMCA (99.51%, credible interval (CI) 97.15-100%) than IHC of obex (brain stem, 76.56%, CI 57.00-91.46%) or retropharyngeal lymph node (90.06%, CI 74.13-98.70%) tissues, or both (98.99%, CI 90.01-100%). Our hierarchical Bayesian model predicts the prevalence of prion infection in this elk population to be 18.90% (CI 15.50-32.72%), compared to previous estimates of 12.90%. Our data reveal a previously unidentified sub-clinical prion-positive portion of the elk population that could represent silent carriers capable of significantly impacting CWD ecology.

  10. Prion protein oligomer and its neurotoxicity

    Institute of Scientific and Technical Information of China (English)

    Pei Huang; Fulin Lian; Yi Wen; Chenyun Guo; Donghai Lin

    2013-01-01

    The prion diseases,also known as transmissible spongiform encephalopathies,are fatal neurodegenerative disorders.According to the 'protein only' hypothesis,the key molecular event in the pathogenesis of prion disease is the conformational conversion of the host-derived cellular prion protein (PrPC) into a misfolded form (scrapie PrP,prpSc).Increasing evidence has shown that the most infectious factor is the smaller subfibrillar oligomers formed by prion proteins.Both the prion oligomer and PrPSc are rich in β-sheet structure and resistant to the proteolysis of proteinase K.The prion oligomer is soluble in physiologic environments whereas PrPSc is insoluble.Various prion oligomers are formed in different conditions.Prion oligomers exhibited more neurotoxicity both in vitro and in vivo than the fibrillar forms of PrPSc,implying that prion oligomers could be potential drug targets for attacking prion diseases.In this article,we describe recent experimental evidence regarding prion oligomers,with a special focus on prion oligomer formation and its neurotoxicity.

  11. Protease-resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion.

    Science.gov (United States)

    Honda, Hiroyuki; Sasaki, Kensuke; Minaki, Haruhiko; Masui, Kenta; Suzuki, Satoshi O; Doh-Ura, Katsumi; Iwaki, Toru

    2012-04-01

    Intraventricular infusion of pentosan polysulfate (PPS) as a treatment for various human prion diseases has been applied in Japan. To evaluate the influence of PPS treatment we performed pathological examination and biochemical analyses of PrP molecules in autopsied brains treated with PPS (one case of sporadic Creutzfeldt-Jakob disease (sCJD, case 1), two cases of dura mater graft-associated CJD (dCJD, cases 2 and 4), and one case of Gerstmann-Sträussler-Scheinker disease (GSS, case 3). Six cases of sCJD without PPS treatment were examined for comparison. Protease-resistant PrP (PrP(res) ) in the frontal lobe was evaluated by Western blotting after proteinase K digestion. Further, the degree of polymerization of PrP molecules was examined by the size-exclusion gel chromatography assay. PPS infusions were started 3-10 months after disease onset, but the treatment did not achieve any clinical improvements. Postmortem examinations of the treated cases revealed symmetrical brain lesions, including neuronal loss, spongiform change and gliosis. Noteworthy was GFAP in the cortical astrocytes reduced in all treated cases despite astrogliosis. Immunohistochemistry for PrP revealed abnormal synaptic deposits in all treated cases and further plaque-type PrP deposition in case 3 of GSS and case 4 of dCJD. Western blotting showed relatively low ratios of PrP(res) in case 2 of dCJD and case 3 of GSS, while in the treated sCJD (case 1), the ratio of PrP(res) was comparable with untreated cases. The indices of oligomeric PrP were reduced in one sCJD (case 1) and one dCJD (case 2). Although intraventricular PPS infusion might modify the accumulation of PrP oligomers in the brains of patients with prion diseases, the therapeutic effects are still uncertain.

  12. Prions mediated neurodegenerative disorders.

    Science.gov (United States)

    Huang, W-J; Chen, W-W; Zhang, X

    2015-11-01

    Prions are unprecedented infectious pathogens that are devoid of nucleic acid and cause a group of rare and invariably fatal neurodegenerative disorders, affecting approximately 1 person per 1 million inhabitants annually worldwide. These disorders include Creutzfeld-Jacob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), kuru, fatal insomnia (FI), and variable protease-sensitive prionopathy (VPSPr), all of which involve a conformational change of the normal cellular prion protein (PrPC) into the abnormal scrapie prion protein (PrPSc) through a posttranslational process during which PrPc acquires high β-sheet content. This structural change is accompanied by profound changes in the physicochemical properties of PrPC, rendering the molecule resistant to proteolysis. The conformational change of PrPC can occur due to either spontaneous conversion, dominant mutations in the prion protein (PRNP) gene encoding PrPC, or infection with pathogenic isoform PrPsc from exogenous sources. There is general agreement that PrPC serves as a substrate for conversion to abnormal PrPSc. This latter multiplies exponentially and aggregates in the brain, forming deposits that are associated with the neurodegenerative changes. Although the understanding of the primary causes of prion-induced neurodegeneration is still limited, propagation of PrPSc and neurotoxic signaling seem to interplay in pathogenic process of prions. Here, we review recent findings that have provided fresh insights into this process, and present an overview of incidence, causes and spectrum of related disorders.

  13. Yeast prions and human prion-like proteins: sequence features and prediction methods.

    Science.gov (United States)

    Cascarina, Sean M; Ross, Eric D

    2014-06-01

    Prions are self-propagating infectious protein isoforms. A growing number of prions have been identified in yeast, each resulting from the conversion of soluble proteins into an insoluble amyloid form. These yeast prions have served as a powerful model system for studying the causes and consequences of prion aggregation. Remarkably, a number of human proteins containing prion-like domains, defined as domains with compositional similarity to yeast prion domains, have recently been linked to various human degenerative diseases, including amyotrophic lateral sclerosis. This suggests that the lessons learned from yeast prions may help in understanding these human diseases. In this review, we examine what has been learned about the amino acid sequence basis for prion aggregation in yeast, and how this information has been used to develop methods to predict aggregation propensity. We then discuss how this information is being applied to understand human disease, and the challenges involved in applying yeast prediction methods to higher organisms.

  14. Doppel: more rival than double to prion.

    Science.gov (United States)

    Qin, K; O'Donnell, M; Zhao, R Y

    2006-08-11

    Conversion of normal cellular prion protein to the diseased form plays an essential role in transmissible spongiform encephalopathies such as mad cow disease and Creutzfeldt-Jakob disease. However, the normal physiological function of prion protein remains elusive. Doppel, a German synonym of double, was initially identified as a prion-like protein due to its structural and biochemical similarities. However, emerging evidence suggests that function of prion protein is more antagonistic to Doppel than synergistic. In this review, basic biochemical and structural similarities of prion protein and Doppel are introduced; evidence demonstrating antagonistic interaction of prion protein with Doppel is presented; and a potential novel activity of Doppel and prion protein in spermatogenesis, which could stimulate new avenues for research, is discussed. PMID:16781817

  15. Protease-sensitive synthetic prions.

    Directory of Open Access Journals (Sweden)

    David W Colby

    2010-01-01

    Full Text Available Prions arise when the cellular prion protein (PrP(C undergoes a self-propagating conformational change; the resulting infectious conformer is designated PrP(Sc. Frequently, PrP(Sc is protease-resistant but protease-sensitive (s prions have been isolated in humans and other animals. We report here that protease-sensitive, synthetic prions were generated in vitro during polymerization of recombinant (rec PrP into amyloid fibers. In 22 independent experiments, recPrP amyloid preparations, but not recPrP monomers or oligomers, transmitted disease to transgenic mice (n = 164, denoted Tg9949 mice, that overexpress N-terminally truncated PrP. Tg9949 control mice (n = 174 did not spontaneously generate prions although they were prone to late-onset spontaneous neurological dysfunction. When synthetic prion isolates from infected Tg9949 mice were serially transmitted in the same line of mice, they exhibited sPrP(Sc and caused neurodegeneration. Interestingly, these protease-sensitive prions did not shorten the life span of Tg9949 mice despite causing extensive neurodegeneration. We inoculated three synthetic prion isolates into Tg4053 mice that overexpress full-length PrP; Tg4053 mice are not prone to developing spontaneous neurological dysfunction. The synthetic prion isolates caused disease in 600-750 days in Tg4053 mice, which exhibited sPrP(Sc. These novel synthetic prions demonstrate that conformational changes in wild-type PrP can produce mouse prions composed exclusively of sPrP(Sc.

  16. Copper Binding in the Prion Protein†

    OpenAIRE

    Millhauser, Glenn L.

    2004-01-01

    A conformational change of the prion protein is responsible for a class of neurodegenerative diseases called the transmissible spongiform encephalopathies that include mad cow disease and the human afflictions kuru and Creutzfeldt–Jakob disease. Despite the attention given to these diseases, the normal function of the prion protein in healthy tissue is unknown. Research over the past few years, however, demonstrates that the prion protein is a copper binding protein with high selectivity for ...

  17. Lymphotoxin-dependent prion replication in inflammatory stromal cells of granulomas.

    Science.gov (United States)

    Heikenwalder, Mathias; Kurrer, Michael O; Margalith, Ilan; Kranich, Jan; Zeller, Nicolas; Haybaeck, Johannes; Polymenidou, Magdalini; Matter, Matthias; Bremer, Juliane; Jackson, Walker S; Lindquist, Susan; Sigurdson, Christina J; Aguzzi, Adriano

    2008-12-19

    Prior to invading the nervous system, prions frequently colonize lymphoid organs and sites of inflammatory lymphoneogenesis, where they colocalize with Mfge8+ follicular dendritic cells (FDCs). Here, we report that soft-tissue granulomas, a frequent feature of chronic inflammation, expressed the cellular prion protein (PrPC, encoded by Prnp) and the lymphotoxin receptor (LTbetaR), even though they lacked FDCs and did not display lymphoneogenesis. After intraperitoneal prion inoculation, granulomas of Prnp(+/+) mice, but not Prnp(-/-) granulomas or unaffected Prnp(+/+) skin, accumulated prion infectivity and disease-associated prion protein. Bone-marrow transfers between Prnp(+/+) and Prnp(-/-) mice and administration of lymphotoxin signaling antagonists indicated that prion replication required radioresistant PrPC-expressing cells and LTbetaR signaling. Granulomatous PrPC was mainly expressed by stromal LTbetaR+ mesenchymal cells that were absent from unaffected subcutis. Hence, granulomas can act as clinically silent reservoirs of prion infectivity. Furthermore, lymphotoxin-dependent prion replication can occur in inflammatory stromal cells that are distinct from FDCs. PMID:19100703

  18. Mouse Models for Studying the Formation and Propagation of Prions*

    OpenAIRE

    Watts, JC; Prusiner, SB

    2014-01-01

    Prions are self-propagating protein conformers that cause a variety of neurodegenerative disorders in humans and animals. Mouse models have played key roles in deciphering the biology of prions and in assessing candidate therapeutics. The development of transgenic mice that form prions spontaneously in the brain has advanced our understanding of sporadic and genetic prion diseases. Furthermore, the realization that many proteins can become prions has necessitated the development of mouse mode...

  19. Detecting and quantifying prions: Mass spectrometry-based approaches

    Science.gov (United States)

    Prions are novel pathogens that cause a set of rare fatal neurological diseases know as transmissible spongiform encephalopathies. Examples of these diseases include Creutzfeldt-Jakob disease, scrapie and chronic wasting disease. Prions are able to recruit a normal cellular prion protein and convert...

  20. SSCP analysis and sequencing of the human prion protein gene (PRNP) detects two different 24 bp deletions in an atypical Alzheimer`s disease family

    Energy Technology Data Exchange (ETDEWEB)

    Perry, R.T.; Go, R.C.P.; Harrell, L.E.; Acton, R.T. [Univ. of Alabama, Birmingham, AL (United States)

    1995-02-27

    Alzheimer`s disease (AD) is a progressive, degenerative neurological disorder of the central nervous system. AD is the fourth leading cause of death in elderly persons 65 years or older in Western industrialized societies. The etiology of AD is unknown, but clinical, pathological, epidemiological, and molecular investigations suggest it is etiologically heterogeneous. Mutations in the amyloid protein are rare and segregate with the disease in a few early-onset familial AD (FAD) families. Similarities between AD and the unconventional viral (UCV) diseases, and between the amyloid and prion proteins, implicate the human prion protein gene (PRNP) as another candidate gene. Single strand conformation polymorphism (SSCP) analysis was used to screen for mutations at this locus in 82 AD patients from 54 families (30 FAD), vs. 39 age-matched controls. A 24-bp deletion around codon 68 that codes for one of five Gly-Pro rich octarepeats was identified in two affected sibs and one offspring of one late-onset FAD family. Two other affected sibs, three unaffected sibs, and three offspring from this family, in addition to one sporadic AD patient and three age-matched controls, were heterozygous for another octarepeat deletion located around codon 82. Two of the four affected sibs had features of PD, including one who was autopsy-verified AD and PD. Although these deletions were found infrequently in other AD patients and controls, they appear to be a rare polymorphism that is segregating in this FAD family. It does not appear that mutations at the PRNP locus are frequently associated with AD in this population. 54 refs., 4 figs.

  1. Distinct patterns of spread of prion infection in brains of mice expressing anchorless or anchored forms of prion protein

    OpenAIRE

    Rangel, Alejandra; Race, Brent; Phillips, Katie; Striebel, James; Kurtz, Nancy; Chesebro, Bruce

    2014-01-01

    Background In humans and animals, prion protein (PrP) is usually expressed as a glycophosphatidylinositol (GPI)-anchored membrane protein, but anchorless PrP may be pathogenic in humans with certain familial prion diseases. Anchored PrP expressed on neurons mediates spread of prions along axons in the peripheral and central nervous systems. However, the mechanism of prion spread in individuals expressing anchorless PrP is poorly understood. Here we studied prion spread within brain of mice ex...

  2. Naturally prion resistant mammals: a utopia?

    Science.gov (United States)

    Fernández-Borges, Natalia; Chianini, Francesca; Eraña, Hasier; Vidal, Enric; Eaton, Samantha L; Pintado, Belén; Finlayson, Jeanie; Dagleish, Mark P; Castilla, Joaquín

    2012-01-01

    Each known abnormal prion protein (PrP (Sc) ) is considered to have a specific range and therefore the ability to infect some species and not others. Consequently, some species have been assumed to be prion disease resistant as no successful natural or experimental challenge infections have been reported. This assumption suggested that, independent of the virulence of the PrP (Sc) strain, normal prion protein (PrP (C) ) from these 'resistant' species could not be induced to misfold. Numerous in vitro and in vivo studies trying to corroborate the unique properties of PrP (Sc) have been undertaken. The results presented in the article "Rabbits are not resistant to prion infection" demonstrated that normal rabbit PrP (C) , which was considered to be resistant to prion disease, can be misfolded to PrP (Sc) and subsequently used to infect and transmit a standard prion disease to leporids. Using the concept of species resistance to prion disease, we will discuss the mistake of attributing species specific prion disease resistance based purely on the absence of natural cases and incomplete in vivo challenges. The BSE epidemic was partially due to an underestimation of species barriers. To repeat this error would be unacceptable, especially if present knowledge and techniques can show a theoretical risk. Now that the myth of prion disease resistance has been refuted it is time to re-evaluate, using the new powerful tools available in modern prion laboratories, whether any other species could be at risk. PMID:22954650

  3. Chronic Lymphocytic Inflammation Specifies the Organ Tropism of Prions

    Science.gov (United States)

    Heikenwalder, Mathias; Zeller, Nicolas; Seeger, Harald; Prinz, Marco; Klöhn, Peter-Christian; Schwarz, Petra; Ruddle, Nancy H.; Weissmann, Charles; Aguzzi, Adriano

    2005-02-01

    Prions typically accumulate in nervous and lymphoid tissues. Because proinflammatory cytokines and immune cells are required for lymphoid prion replication, we tested whether inflammatory conditions affect prion pathogenesis. We administered prions to mice with five inflammatory diseases of the kidney, pancreas, or liver. In all cases, chronic lymphocytic inflammation enabled prion accumulation in otherwise prion-free organs. Inflammatory foci consistently correlated with lymphotoxin up-regulation and ectopic induction of FDC-M1+ cells expressing the normal cellular prion protein PrPC. By contrast, inflamed organs of mice lacking lymphotoxin-α or its receptor did not accumulate the abnormal isoform PrPSc, nor did they display infectivity upon prion inoculation. By expanding the tissue distribution of prions, chronic inflammatory conditions may act as modifiers of natural and iatrogenic prion transmission.

  4. Detection of prions in the faeces of sheep naturally infected with classical scrapie

    Directory of Open Access Journals (Sweden)

    Terry Linda A

    2011-05-01

    Full Text Available Abstract Classical scrapie is a naturally transmitted prion disease of sheep and goats. Contaminated environments may contribute to the spread of disease and evidence from animal models has implicated urine, blood, saliva, placenta and faeces as possible sources of the infection. Here we sought to determine whether sheep naturally infected with classical scrapie shed prions in their faeces. We used serial protein misfolding cyclic amplification (sPMCA along with two extraction methods to examine faeces from sheep during both the clinical and preclinical phases of the disease and showed amplification of PrPSc in 7 of 15 and 14 of 14 sheep respectively. However PrPSc was not amplified from the faeces of 25 sheep not exposed to scrapie. These data represent the first demonstration of prion shedding in faeces from a naturally infected host and thus a likely source of prion contamination in the environment.

  5. COMPOSITE PEPTIDE COMPOUNDS FOR DIAGNOSIS AND TREATMENT OF DISEASES CAUSED BY PRION PROTEINS

    DEFF Research Database (Denmark)

    2004-01-01

    that they together form a non-linear sequence which mimics the tertiary structure of one or more PrPSc-specific epitopes as evidenced by the test described herein. The use of such conjugates as immunogens for the production of antibodies that specifically bind to the pathogenic form of a prion protein is revealed...

  6. Regional brain metabolite abnormalities in inherited prion disease and asymptomatic gene carriers demonstrated in vivo by quantitative proton magnetic resonance spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Waldman, A.D.; Cordery, R.J.; Godbolt, A.; Rossor, M.N. [University College London, Dementia Research Group, Department of Neurodegenerative Disease, Institute of Neurology, London (United Kingdom); Imperial College of Science, Technology and Medicine, Division of Neuroscience and Psychological Medicine, Faculty of Medicine, London (United Kingdom); MacManus, D.G. [University College London, NMR Research Unit, Department of Clinical Neurology, Institute of Neurology, London (United Kingdom); Collinge, J. [University College London, MRC Prion Unit, Department of Neurodegenerative Disease, Institute of Neurology, London (United Kingdom)

    2006-06-15

    Inherited prion diseases are caused by mutations in the gene which codes for prion protein (PrP), leading to proliferation of abnormal PrP isomers in the brain and neurodegeneration; they include Gerstmann-Straeussler-Scheinker disease (GSS), fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). We studied two patients with symptomatic inherited prion disease (P102L) and two pre-symptomatic P102L gene carriers using quantitative magnetic resonance spectroscopy (MRS). Short echo time spectra were acquired from the thalamus, caudate region and frontal white matter, metabolite levels and ratios were measured and z-scores calculated for individual patients relative to age-matched normal controls. MRS data were compared with structural magnetic resonance imaging. One fCJD case had generalised atrophy and showed increased levels of myo-inositol (MI) in the thalamus (z=3.7). The other had decreased levels of N-acetylaspartate (z=4) and diffuse signal abnormality in the frontal white matter. Both asymptomatic gene carriers had normal imaging, but increased frontal white matter MI (z=4.3, 4.1), and one also had increased MI in the caudate (z=5.3). Isolated MI abnormalities in asymptomatic gene carriers are a novel finding and may reflect early glial proliferation, prior to significant neuronal damage. MRS provides potential non-invasive surrogate markers of early disease and progression in inherited prion disease. (orig.)

  7. Regional brain metabolite abnormalities in inherited prion disease and asymptomatic gene carriers demonstrated in vivo by quantitative proton magnetic resonance spectroscopy

    International Nuclear Information System (INIS)

    Inherited prion diseases are caused by mutations in the gene which codes for prion protein (PrP), leading to proliferation of abnormal PrP isomers in the brain and neurodegeneration; they include Gerstmann-Straeussler-Scheinker disease (GSS), fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). We studied two patients with symptomatic inherited prion disease (P102L) and two pre-symptomatic P102L gene carriers using quantitative magnetic resonance spectroscopy (MRS). Short echo time spectra were acquired from the thalamus, caudate region and frontal white matter, metabolite levels and ratios were measured and z-scores calculated for individual patients relative to age-matched normal controls. MRS data were compared with structural magnetic resonance imaging. One fCJD case had generalised atrophy and showed increased levels of myo-inositol (MI) in the thalamus (z=3.7). The other had decreased levels of N-acetylaspartate (z=4) and diffuse signal abnormality in the frontal white matter. Both asymptomatic gene carriers had normal imaging, but increased frontal white matter MI (z=4.3, 4.1), and one also had increased MI in the caudate (z=5.3). Isolated MI abnormalities in asymptomatic gene carriers are a novel finding and may reflect early glial proliferation, prior to significant neuronal damage. MRS provides potential non-invasive surrogate markers of early disease and progression in inherited prion disease. (orig.)

  8. Classifying prion and prion-like phenomena.

    Science.gov (United States)

    Harbi, Djamel; Harrison, Paul M

    2014-01-01

    The universe of prion and prion-like phenomena has expanded significantly in the past several years. Here, we overview the challenges in classifying this data informatically, given that terms such as "prion-like", "prion-related" or "prion-forming" do not have a stable meaning in the scientific literature. We examine the spectrum of proteins that have been described in the literature as forming prions, and discuss how "prion" can have a range of meaning, with a strict definition being for demonstration of infection with in vitro-derived recombinant prions. We suggest that although prion/prion-like phenomena can largely be apportioned into a small number of broad groups dependent on the type of transmissibility evidence for them, as new phenomena are discovered in the coming years, a detailed ontological approach might be necessary that allows for subtle definition of different "flavors" of prion / prion-like phenomena.

  9. Temporal resolution of PrPSc transport, PrPSc accumulation, activation of glia and neuronal death in retinas from C57Bl/6 mice inoculated with RML scrapie: Relevance to biomarkers of prion disease progression

    Science.gov (United States)

    Currently, there is a lack of pathologic landmarks to objectively evaluate the progression of prion disease in vivo. The goal of this work was to determine the temporal relationship between transport of misfolded prion protein to the retina from the brain, accumulation of PrPSc in the retina, the re...

  10. Current concepts and controversies in prion immunopathology.

    Science.gov (United States)

    Heikenwalder, Mathias; Prinz, Marco; Heppner, Frank L; Aguzzi, Adriano

    2004-01-01

    Scrapie in sheep and new variant Creutzfeldt-Jakob disease in humans are typically initiated by extracerebral exposure to prions. Both exhibit early prion accumulation in sites of the peripheral lymphoreticular system, such as splenic or lymph nodal germinal centers. In germinal centers, follicular dendritic cells (FDCs), whose development and maintenance depend on lymphotoxin and tumor necrosis factor signaling, are believed to be the main cell type for efficient prion replication in the periphery. Here, we discuss the molecular requirements for prion replication competence in stromal and lymphoid compartments of lymphoid organs. In addition, we examine the preconditions of transepithelial passage of prions in the mucosal-associated lymphoid system. Our results suggest that under specific conditions, efficient prion replication in mesenteric and inguinal lymph nodes is possible in the absence of mature FDCs. M cells are a plausible candidate for the mucosal portal of prion infection. PMID:15126687

  11. Secretory pathway retention of mutant prion protein induces p38-MAPK activation and lethal disease in mice.

    Science.gov (United States)

    Puig, Berta; Altmeppen, Hermann C; Ulbrich, Sarah; Linsenmeier, Luise; Krasemann, Susanne; Chakroun, Karima; Acevedo-Morantes, Claudia Y; Wille, Holger; Tatzelt, Jörg; Glatzel, Markus

    2016-01-01

    Misfolding of proteins in the biosynthetic pathway in neurons may cause disturbed protein homeostasis and neurodegeneration. The prion protein (PrP(C)) is a GPI-anchored protein that resides at the plasma membrane and may be misfolded to PrP(Sc) leading to prion diseases. We show that a deletion in the C-terminal domain of PrP(C) (PrPΔ214-229) leads to partial retention in the secretory pathway causing a fatal neurodegenerative disease in mice that is partially rescued by co-expression of PrP(C). Transgenic (Tg(PrPΔ214-229)) mice show extensive neuronal loss in hippocampus and cerebellum and activation of p38-MAPK. In cell culture under stress conditions, PrPΔ214-229 accumulates in the Golgi apparatus possibly representing transit to the Rapid ER Stress-induced ExporT (RESET) pathway together with p38-MAPK activation. Here we describe a novel pathway linking retention of a GPI-anchored protein in the early secretory pathway to p38-MAPK activation and a neurodegenerative phenotype in transgenic mice. PMID:27117504

  12. Prion pathogenesis and secondary lymphoid organs (SLO): Tracking the SLO spread of prions to the brain

    OpenAIRE

    Mabbott, N A

    2012-01-01

    Prion diseases are subacute neurodegenerative diseases that affect humans and a range of domestic and free-ranging animal species. These diseases are characterized by the accumulation of PrP (Sc) , an abnormally folded isoform of the cellular prion protein (PrP (C) ), in affected tissues. The pathology during prion disease appears to occur almost exclusively within the central nervous system. The extensive neurodegeneration which occurs ultimately leads to the death of the host. An intriguing...

  13. Prions: the danger of biochemical weapons

    OpenAIRE

    Eric Almeida Xavier

    2014-01-01

    The knowledge of biotechnology increases the risk of using biochemical weapons for mass destruction. Prions are unprecedented infectious pathogens that cause a group of fatal neurodegenerative diseases by a novel mechanism. They are transmissible particles that are devoid of nucleic acid. Due to their singular characteristics, Prions emerge as potential danger since they can be used in the development of such weapons. Prions cause fatal infectious diseases, and to date there is no therapeutic...

  14. Species Barrier Prevents an Abnormal Isoform of Prion Protein from Accumulating in Follicular Dendritic Cells of Mice with Creutzfeldt-Jakob Disease

    OpenAIRE

    Muramoto, Tamaki; Kitamoto, Tetsuyuki; Hoque, Mohammad Zahirul; Tateishi, Jun; Goto, Ikuo

    1993-01-01

    The accumulation of abnormal prion protein in follicular dendritic cells did not occur in mice inoculated with materials from human Creutzfeldt-Jakob disease, whereas it always occurred in mice inoculated with mouse-adapted agents, suggesting an intense expression of the species barrier in the lymphoreticular system.

  15. Unaltered Prion Pathogenesis in a Mouse Model of High-Fat Diet-Induced Insulin Resistance.

    Directory of Open Access Journals (Sweden)

    Caihong Zhu

    Full Text Available Epidemiological, clinical, and experimental animal studies suggest a strong correlation between insulin resistance and Alzheimer's disease. In fact, type-2 diabetes is considered an important risk factor of developing Alzheimer's disease. In addition, impaired insulin signaling in the Alzheimer's disease brain may promote Aβ production, impair Aβ clearance and induce tau hyperphosphorylation, thereby leading to deterioration of the disease. The pathological prion protein, PrPSc, deposits in the form of extracellular aggregates and leads to dementia, raising the question as to whether prion pathogenesis may also be affected by insulin resistance. We therefore established high-fat diet-induced insulin resistance in tga20 mice, which overexpress the prion protein. We then inoculated the insulin-resistant mice with prions. We found that insulin resistance in tga20 mice did not affect prion disease progression, PrPSc deposition, astrogliosis or microglial activation, and had no effect on survival. Our study demonstrates that in a mouse model, insulin resistance does not significantly contribute to prion pathogenesis.

  16. Prions and the blood and immune systems.

    Science.gov (United States)

    Mabbott, Neil; Turner, Marc

    2005-04-01

    Prion diseases take a number of forms in animals and humans. They are caused by conformational change in widely expressed prion protein leading to the formation of intracellular aggregates. Although the main focus of disease is the central nervous system, it is known that involvement of the immune system occurs in peripherally transmitted disease in particular. Animal experiments suggest that in some prion diseases follicular dendritic cells in the germinal centers are a major site of initial accumulation, and that abnormal prion protein and infectivity are detectable in peripheral lymphoid tissue from the earliest phase of disease. This raises the possibility that in a human peripherally transmitted prion disease like variant Creutzfeldt-Jakob disease, further transmission could occur through blood or tissue products or contamination of surgical instrumentation. Indeed two recent reports confirm that this disease has been transmitted by blood, raising significant public health concerns. PMID:15820951

  17. Yeast and Fungal Prions: Amyloid-Handling Systems, Amyloid Structure, and Prion Biology.

    Science.gov (United States)

    Wickner, R B; Edskes, H K; Gorkovskiy, A; Bezsonov, E E; Stroobant, E E

    2016-01-01

    Yeast prions (infectious proteins) were discovered by their outré genetic properties and have become important models for an array of human prion and amyloid diseases. A single prion protein can become any of many distinct amyloid forms (called prion variants or strains), each of which is self-propagating, but with different biological properties (eg, lethal vs mild). The folded in-register parallel β sheet architecture of the yeast prion amyloids naturally suggests a mechanism by which prion variant information can be faithfully transmitted for many generations. The yeast prions rely on cellular chaperones for their propagation, but can be cured by various chaperone imbalances. The Btn2/Cur1 system normally cures most variants of the [URE3] prion that arise. Although most variants of the [PSI+] and [URE3] prions are toxic or lethal, some are mild in their effects. Even the most mild forms of these prions are rare in the wild, indicating that they too are detrimental to yeast. The beneficial [Het-s] prion of Podospora anserina poses an important contrast in its structure, biology, and evolution to the yeast prions characterized thus far.

  18. Comparison of CR36, a new heparan mimetic, and pentosan polysulfate in the treatment of prion diseases.

    Science.gov (United States)

    Larramendy-Gozalo, Claire; Barret, Agnès; Daudigeos, Estelle; Mathieu, Emilie; Antonangeli, Lucie; Riffet, Cécile; Petit, Emmanuel; Papy-Garcia, Dulce; Barritault, Denis; Brown, Paul; Deslys, Jean-Philippe

    2007-03-01

    Sulfated polyanions, including pentosan polysulfate (PPS) and heparan mimetics, number among the most effective drugs that have been used in experimental models of prion disease and are presumed to act in competition with endogenous heparan sulfate proteoglycans as co-receptors for prion protein (PrP) on the cell surface. PPS has been shown to prolong the survival of animals after intracerebral perfusion and is in limited use for the experimental treatment of human transmissible spongiform encephalopathies (TSEs). Here, PPS is compared with CR36, a new heparan mimetic. Ex vivo, CR36 was more efficient than PPS in reducing PrPres in scrapie-infected cell cultures and showed long-lasting activity. In vivo, CR36 showed none of the acute toxicity observed with PPS and reduced PrPres accumulation in spleens, but had only a marginal effect on the survival time of mice infected with bovine spongiform encephalopathy. In contrast, mice treated with PPS that survived the initial toxic mortality had no detectable PrPres in the spleens and lived 185 days longer than controls (+55%). These results show, once again, that anti-TSE drugs cannot be encouraged for human therapeutic trials solely on the basis of in vitro or ex vivo observations, but must first be subjected to in vivo animal studies.

  19. Prions in Variably Protease-Sensitive Prionopathy: An Update

    NARCIS (Netherlands)

    Zou, W.Q.; Gambetti, P.; Xiao, X.; Yuan, J.; Langeveld, J.P.M.; Pirisinu, L.

    2013-01-01

    Human prion diseases, including sporadic, familial, and acquired forms such as Creutzfeldt-Jakob disease (CJD), are caused by prions in which an abnormal prion protein (PrPSc) derived from its normal cellular isoform (PrPC) is the only known component. The recently-identified variably protease-sensi

  20. Mass Spectrometry of Prions: Approaches to Conformational Distinction

    Science.gov (United States)

    Prions are the agents that cause a set of fatal neurological diseases that include Creutzfeldt-Jakob disease. Prions are composed solely of protein. Unlike viral, bacterial, or fungal pathogens, the information necessary to propagate the infection is contained in the conformation of the prion isofor...

  1. Lichens: unexpected anti-prion agents?

    Science.gov (United States)

    Rodriguez, Cynthia M.; Bennett, James P.; Johnson, Christopher J.

    2012-01-01

    The prion diseases sheep scrapie and cervid chronic wasting disease are transmitted, in part, via an environmental reservoir of infectivity; prions released from infected animals persist in the environment and can cause disease years later. Central to controlling disease transmission is the identification of methods capable of inactivating these agents on the landscape. We have found that certain lichens, common, ubiquitous, symbiotic organisms, possess a serine protease capable of degrading prion protein (PrP) from prion-infected animals. The protease functions against a range of prion strains from various hosts and reduces levels of abnormal PrP by at least two logs. We have now tested more than 20 lichen species from several geographical locations and from various taxa and found that approximately half of these species degrade PrP. Critical next steps include examining the effect of lichens on prion infectivity and cloning the protease responsible for PrP degradation. The impact of lichens on prions in the environment remains unknown. We speculate that lichens could have the potential to degrade prions when they are shed from infected animals onto lichens or into environments where lichens are abundant. In addition, lichens are frequently consumed by cervids and many other animals and the effect of dietary lichens on prion disease transmission should also be considered.

  2. Accumulation and dissemination of prion protein in experimental sheep scrapie in the natural host

    Directory of Open Access Journals (Sweden)

    Warner Richard

    2009-02-01

    Full Text Available Abstract Background In order to study the sites of uptake and mechanisms of dissemination of scrapie prions in the natural host under controlled conditions, lambs aged 14 days and homozygous for the VRQ allele of the PrP gene were infected by the oral route. Infection occurred in all lambs with a remarkably short and highly consistent incubation period of approximately 6 months. Challenge of lambs at approximately eight months of age resulted in disease in all animals, but with more variable incubation periods averaging significantly longer than those challenged at 14 days. This model provides an excellent system in which to study the disease in the natural host by virtue of the relatively short incubation period and close resemblance to natural infection. Results Multiple sites of prion uptake were identified, of which the most important was the Peyer's patch of the distal ileum. Neuroinvasion was detected initially in the enteric nervous system prior to infection of the central nervous system. At end stage disease prion accumulation was widespread throughout the entire neuraxis, but vacuolar pathology was absent in most animals that developed disease at 6–7 months of age. Conclusion Initial spread of detectable PrP was consistent with drainage in afferent lymph to dependent lymph nodes. Subsequent accumulation of prions in lymphoid tissue not associated with the gut is consistent with haematogenous spread. In addition to macrophages and follicular dendritic cells, prion containing cells consistent with afferent lymph dendritic cells were identified and are suggested as a likely vehicle for carriage of prions from initial site of uptake to the lymphoreticular system, and as potential carriers of prion protein in blood. It is apparent that spongiform change, the characteristic lesion of scrapie and other prion diseases, is not responsible for the clinical signs in sheep, but may develop in an age dependent manner.

  3. Chronic Wasting Disease in Bank Voles: Characterisation of the Shortest Incubation Time Model for Prion Diseases

    NARCIS (Netherlands)

    Bari, Di M.A.; Nonno, R.; Castilla, J.; Augostino, D' C.; Pirisinu, L.; Riccardi, G.; Conte, M.; Richt, J.A.; Kunkle, R.; Langeveld, J.P.M.; Vaccari, G.; Agrimi, U.

    2013-01-01

    In order to assess the susceptibility of bank voles to chronic wasting disease (CWD), we inoculated voles carrying isoleucine or methionine at codon 109 (Bv109I and Bv109M, respectively) with CWD isolates from elk, mule deer and white-tailed deer. Efficient transmission rate (100%) was observed with

  4. Rare Diseases Clinical Research Network

    Science.gov (United States)

    ... RDCRN? Aims of the Rare Diseases Clinical Research Network Contact Us RDCRN Members Login Accessibility Disclaimer The Rare Diseases Clinical Research Network is an initiative of the Office of Rare ...

  5. Localization of disease-related PrP in Danish patients with different subtypes of prion disease

    DEFF Research Database (Denmark)

    Bergström, A. L.; Heegaard, Peter M. H.; Dyrbye, H.;

    2009-01-01

    Objective: The transmissible spongiform encephalopaties are characterized by vacuolization, neuronal loss, gliosis and deposition of a misfilded and Proteinase K resistant isoform of the prion protein (PrPSc) in the central nervous system. Methods, materials and patients: Paraffin-embedded tissue...

  6. Localization of disease-related PrP in Danish patients with different subtypes of prion disease

    DEFF Research Database (Denmark)

    Bergstrom, A.L.; Heegaard, P.M.; Dyrbye, H.;

    2009-01-01

    OBJECTIVE: The transmissible spongiform encephalopathies are characterized by vacuolization, neuronal loss, gliosis and deposition of a misfolded and Proteinase K resistant isoform of the prion protein (PrP(Sc)) in the central nervous system. METHODS MATERIALS AND PATIENTS: Paraffin-embedded tiss...

  7. 加强对朊病毒的研究和朊病毒病的防控%Enforcement of prion research and prevalence of prion disease

    Institute of Scientific and Technical Information of China (English)

    董小平

    2007-01-01

    朊病毒病(prion disease),又称可传播性海绵状脑病(Transmissible spongiform encephalopathies,TSE),是一类侵袭人类及多种动物中枢神经系统的传染性退行性脑病,潜伏期长,病死率100%。

  8. Viruses and prions of Saccharomyces cerevisiae

    OpenAIRE

    Wickner, Reed B.; Fujimura, Tsutomu; Esteban, Rosa

    2013-01-01

    Saccharomyces cerevisiae has been a key experimental organism for the study of infectious diseases, including dsRNA viruses, ssRNA viruses, and prions. Studies of the mechanisms of virus and prion replication, virus structure, and structure of the amyloid filaments that are the basis of yeast prions have been at the forefront of such studies in these classes of infectious entities. Yeast has been particularly useful in defining the interactions of the infectious elements with cellular compone...

  9. Current concepts and controversies in prion immunopathology.

    OpenAIRE

    Heikenwalder, M.; Prinz, M.; Heppner, F.L.; Aguzzi, A

    2004-01-01

    Scrapie in sheep and new variant Creutzfeldt-Jakob disease in humans are typically initiated by extracerebral exposure to prions. Both exhibit early prion accumulation in sites of the peripheral lymphoreticular system, such as splenic or lymph nodal germinal centers. In germinal centers, follicular dendritic cells (FDCs), whose development and maintenance depend on lymphotoxin and tumor necrosis factor signaling, are believed to be the main cell type for efficient prion replication in the per...

  10. Extraneural Prion Neuroinvasion without Lymphoreticular System Infection

    OpenAIRE

    Bartz, Jason C.; DeJoia, Crista; Tucker, Tammy; Kincaid, Anthony E.; Bessen, Richard A.

    2005-01-01

    While prion infection of the lymphoreticular system (LRS) is necessary for neuroinvasion in many prion diseases, in bovine spongiform encephalopathy and atypical cases of sheep scrapie there is evidence to challenge that LRS infection is required for neuroinvasion. Here we investigated the role of prion infection of LRS tissues in neuroinvasion following extraneural inoculation with the HY and DY strains of the transmissible mink encephalopathy (TME) agent. DY TME agent infectivity was not de...

  11. Review: A review on classical and atypical scrapie in caprine: Prion protein gene polymorphisms and their role in the disease.

    Science.gov (United States)

    Curcio, L; Sebastiani, C; Di Lorenzo, P; Lasagna, E; Biagetti, M

    2016-10-01

    Scrapie is a naturally occurring transmissible spongiform encephalopathy in sheep and goat. It has been known for ~250 years and is characterised by the accumulation of an abnormal isoform of a host-encoded prion protein that leads to progressive neurodegeneration and death. Scrapie is recognised in two forms, classical and atypical scrapie. The susceptibility to both types of scrapie is influenced by polymorphisms of the prion protein gene (PRNP). Sheep susceptibility or resistance to classical scrapie is strongly regulated by the polymorphisms at codons 136, 154 and 171 of the PRNP. The genetic role in atypical scrapie in sheep has been defined by polymorphisms at codons 141, 154 and 171, which are associated with different degrees of risk in the occurrence of the ovine disease. Progress has been achieved in the prevention of scrapie in sheep due to efficient genetic breeding programmes based on eradication and control of the disease. In Europe, the success of these programmes has been verified by applying eradication and genetic selection plans. In general terms, the ovine selection plans aim to eliminate and reduce the susceptible allele and to enrich the resistant allele ARR. During outbreaks all susceptible animals are slaughtered, only ARR/ARR resistant rams and sheep and semi-resistant females are preserved. In the occurrence of scrapie positive goats a complete cull of the flock (stamping out) is performed with great economic loss and severe risk of extinction for the endangered breeds. The ability to select scrapie-resistant animals allows to define new breeding strategies aimed to boost genetic progress while reducing costs during scrapie outbreaks. Allelic variants of PRNP can be protective for caprine scrapie, and the knowledge of their distribution in goats has become very important. Over the past few years, the integration of genetic information on goat populations could be used to make selection decisions, commonly referred to as genetic selection

  12. Detection of prion infectivity in fat tissues of scrapie-infected mice.

    Directory of Open Access Journals (Sweden)

    Brent Race

    2008-12-01

    Full Text Available Distribution of prion infectivity in organs and tissues is important in understanding prion disease pathogenesis and designing strategies to prevent prion infection in animals and humans. Transmission of prion disease from cattle to humans resulted in banning human consumption of ruminant nervous system and certain other tissues. In the present study, we surveyed tissue distribution of prion infectivity in mice with prion disease. We show for the first time detection of infectivity in white and brown fat. Since high amounts of ruminant fat are consumed by humans and also incorporated into animal feed, fat-containing tissues may pose a previously unappreciated hazard for spread of prion infection.

  13. Molecular Dynamics Studies on the Buffalo Prion Protein

    CERN Document Server

    Zhang, Jiapu

    2015-01-01

    It was reported that buffalo is a low susceptibility species resisting to TSEs (Transmissible Spongiform Encephalopathies) (same as rabbits, horses and dogs). TSEs, also called prion diseases, are invariably fatal and highly infectious neurodegenerative diseases that affect a wide variety of species (in humans prion diseases are (v)CJDs, GSS, FFI, and kulu etc). It was reported that buffalo is a low susceptibility species resisting to prion diseases (as rabbits, dogs, horses). In molecular structures, these neurodegenerative diseases are caused by the conversion from a soluble normal cellular prion protein, predominantly with alpha-helices, into insoluble abnormally folded infectious prions, rich in beta-sheets. This paper studies the molecular structure and structural dynamics of buffalo prion protein, in order to find out the reason why buffaloes are resistant to prion diseases. We first did molecular modeling a homology structure constructed by one mutation at residue 143 from the Nuclear Magnetic Resonanc...

  14. Accelerated high fidelity prion amplification within and across prion species barriers.

    Directory of Open Access Journals (Sweden)

    Kristi M Green

    Full Text Available Experimental obstacles have impeded our ability to study prion transmission within and, more particularly, between species. Here, we used cervid prion protein expressed in brain extracts of transgenic mice, referred to as Tg(CerPrP, as a substrate for in vitro generation of chronic wasting disease (CWD prions by protein misfolding cyclic amplification (PMCA. Characterization of this infectivity in Tg(CerPrP mice demonstrated that serial PMCA resulted in the high fidelity amplification of CWD prions with apparently unaltered properties. Using similar methods to amplify mouse RML prions and characterize the resulting novel cervid prions, we show that serial PMCA abrogated a transmission barrier that required several hundred days of adaptation and subsequent stabilization in Tg(CerPrP mice. While both approaches produced cervid prions with characteristics distinct from CWD, the subtly different properties of the resulting individual prion isolates indicated that adaptation of mouse RML prions generated multiple strains following inter-species transmission. Our studies demonstrate that combined transgenic mouse and PMCA approaches not only expedite intra- and inter-species prion transmission, but also provide a facile means of generating and characterizing novel prion strains.

  15. Urinary alpha1-antichymotrypsin: a biomarker of prion infection.

    Directory of Open Access Journals (Sweden)

    Gino Miele

    Full Text Available The occurrence of blood-borne prion transmission incidents calls for identification of potential prion carriers. However, current methods for intravital diagnosis of prion disease rely on invasive tissue biopsies and are unsuitable for large-scale screening. Sensitive biomarkers may help meeting this need. Here we scanned the genome for transcripts elevated upon prion infection and encoding secreted proteins. We found that alpha(1-antichymotrypsin (alpha(1-ACT was highly upregulated in brains of scrapie-infected mice. Furthermore, alpha(1-ACT levels were dramatically increased in urine of patients suffering from sporadic Creutzfeldt-Jakob disease, and increased progressively throughout the disease. Increased alpha(1-ACT excretion was also found in cases of natural prion disease of animals. Therefore measurement of urinary alpha(1-ACT levels may be useful for monitoring the efficacy of therapeutic regimens for prion disease, and possibly also for deferring blood and organ donors that may be at risk of transmitting prion infections.

  16. Accelerating Yeast Prion Biology using Droplet Microfluidics

    Science.gov (United States)

    Ung, Lloyd; Rotem, Assaf; Jarosz, Daniel; Datta, Manoshi; Lindquist, Susan; Weitz, David

    2012-02-01

    Prions are infectious proteins in a misfolded form, that can induce normal proteins to take the misfolded state. Yeast prions are relevant, as a model of human prion diseases, and interesting from an evolutionary standpoint. Prions may also be a form of epigenetic inheritance, which allow yeast to adapt to stressful conditions at rates exceeding those of random mutations and propagate that adaptation to their offspring. Encapsulation of yeast in droplet microfluidic devices enables high-throughput measurements with single cell resolution, which would not be feasible using bulk methods. Millions of populations of yeast can be screened to obtain reliable measurements of prion induction and loss rates. The population dynamics of clonal yeast, when a fraction of the cells are prion expressing, can be elucidated. Furthermore, the mechanism by which certain strains of bacteria induce yeast to express prions in the wild can be deduced. Integrating the disparate fields of prion biology and droplet microfluidics reveals a more complete picture of how prions may be more than just diseases and play a functional role in yeast.

  17. Disease-associated prion protein in neural and lymphoid tissues of mink (Mustela vison) inoculated with transmissible mink encephalopathy

    Science.gov (United States)

    Transmissible mink encephalopathy (TME) is a prion disorder of farmed raised mink. As with the other transmissible spongiform encephalopathies, the disorder is associated with accumulation of the misfolded prion protein in the brain and an invariably fatal outcome. TME outbreaks have been rare but...

  18. Intraperitoneal Infection of Wild-Type Mice with Synthetically Generated Mammalian Prion.

    Directory of Open Access Journals (Sweden)

    Xinhe Wang

    2015-07-01

    Full Text Available The prion hypothesis postulates that the infectious agent in transmissible spongiform encephalopathies (TSEs is an unorthodox protein conformation based agent. Recent successes in generating mammalian prions in vitro with bacterially expressed recombinant prion protein provide strong support for the hypothesis. However, whether the pathogenic properties of synthetically generated prion (rec-Prion recapitulate those of naturally occurring prions remains unresolved. Using end-point titration assay, we showed that the in vitro prepared rec-Prions have infectious titers of around 104 LD50/μg. In addition, intraperitoneal (i.p. inoculation of wild-type mice with rec-Prion caused prion disease with an average survival time of 210-220 days post inoculation. Detailed pathological analyses revealed that the nature of rec-Prion induced lesions, including spongiform change, disease specific prion protein accumulation (PrP-d and the PrP-d dissemination amongst lymphoid and peripheral nervous system tissues, the route and mechanisms of neuroinvasion were all typical of classical rodent prions. Our results revealed that, similar to naturally occurring prions, the rec-Prion has a titratable infectivity and is capable of causing prion disease via routes other than direct intra-cerebral challenge. More importantly, our results established that the rec-Prion caused disease is pathogenically and pathologically identical to naturally occurring contagious TSEs, supporting the concept that a conformationally altered protein agent is responsible for the infectivity in TSEs.

  19. Intraperitoneal Infection of Wild-Type Mice with Synthetically Generated Mammalian Prion.

    Science.gov (United States)

    Wang, Xinhe; McGovern, Gillian; Zhang, Yi; Wang, Fei; Zha, Liang; Jeffrey, Martin; Ma, Jiyan

    2015-07-01

    The prion hypothesis postulates that the infectious agent in transmissible spongiform encephalopathies (TSEs) is an unorthodox protein conformation based agent. Recent successes in generating mammalian prions in vitro with bacterially expressed recombinant prion protein provide strong support for the hypothesis. However, whether the pathogenic properties of synthetically generated prion (rec-Prion) recapitulate those of naturally occurring prions remains unresolved. Using end-point titration assay, we showed that the in vitro prepared rec-Prions have infectious titers of around 104 LD50/μg. In addition, intraperitoneal (i.p.) inoculation of wild-type mice with rec-Prion caused prion disease with an average survival time of 210-220 days post inoculation. Detailed pathological analyses revealed that the nature of rec-Prion induced lesions, including spongiform change, disease specific prion protein accumulation (PrP-d) and the PrP-d dissemination amongst lymphoid and peripheral nervous system tissues, the route and mechanisms of neuroinvasion were all typical of classical rodent prions. Our results revealed that, similar to naturally occurring prions, the rec-Prion has a titratable infectivity and is capable of causing prion disease via routes other than direct intra-cerebral challenge. More importantly, our results established that the rec-Prion caused disease is pathogenically and pathologically identical to naturally occurring contagious TSEs, supporting the concept that a conformationally altered protein agent is responsible for the infectivity in TSEs.

  20. Atypical scrapie isolates involve a uniform prion species with a complex molecular signature.

    Directory of Open Access Journals (Sweden)

    Dorothea R Götte

    Full Text Available The pathobiology of atypical scrapie, a prion disease affecting sheep and goats, is still poorly understood. In a previous study, we demonstrated that atypical scrapie affecting small ruminants in Switzerland differs in the neuroanatomical distribution of the pathological prion protein (PrP(d. To investigate whether these differences depend on host-related vs. pathogen-related factors, we transmitted atypical scrapie to transgenic mice over-expressing the ovine prion protein (tg338. The clinical, neuropathological, and molecular phenotype of tg338 mice is similar between mice carrying the Swiss atypical scrapie isolates and the Nor98, an atypical scrapie isolate from Norway. Together with published data, our results suggest that atypical scrapie is caused by a uniform type of prion, and that the observed phenotypic differences in small ruminants are likely host-dependant. Strikingly, by using a refined SDS-PAGE technique, we established that the prominent proteinase K-resistant prion protein fragment in atypical scrapie consists of two separate, unglycosylated peptides with molecular masses of roughly 5 and 8 kDa. These findings show similarities to those for other prion diseases in animals and humans, and lay the groundwork for future comparative research.

  1. Effects of Solution Chemistry and Aging Time on Prion Protein Adsorption and Replication of Soil-Bound Prions

    OpenAIRE

    Samuel E Saunders; Yuan, Qi; Bartz, Jason C.; Bartelt-Hunt, Shannon

    2011-01-01

    Prion interactions with soil may play an important role in the transmission of chronic wasting disease (CWD) and scrapie. Prions are known to bind to a wide range of soil surfaces, but the effects of adsorption solution chemistry and long-term soil binding on prion fate and transmission risk are unknown. We investigated HY TME prion protein (PrPSc) adsorption to soil minerals in aqueous solutions of phosphate buffered saline (PBS), sodium chloride, calcium chloride, and deionized water using ...

  2. Prion pathogenesis and secondary lymphoid organs (SLO): tracking the SLO spread of prions to the brain.

    Science.gov (United States)

    Mabbott, Neil A

    2012-01-01

    Prion diseases are subacute neurodegenerative diseases that affect humans and a range of domestic and free-ranging animal species. These diseases are characterized by the accumulation of PrP (Sc), an abnormally folded isoform of the cellular prion protein (PrP (C)), in affected tissues. The pathology during prion disease appears to occur almost exclusively within the central nervous system. The extensive neurodegeneration which occurs ultimately leads to the death of the host. An intriguing feature of the prion diseases, when compared with other protein-misfolding diseases, is their transmissibility. Following peripheral exposure, some prion diseases accumulate to high levels within lymphoid tissues. The replication of prions within lymphoid tissue has been shown to be important for the efficient spread of disease to the brain. This article describes recent progress in our understanding of the cellular mechanisms that influence the propagation of prions from peripheral sites of exposure (such as the lumen of the intestine) to the brain. A thorough understanding of these events will lead to the identification of important targets for therapeutic intervention, or alternatively, reveal additional processes that influence disease susceptibility to peripherally-acquired prion diseases.

  3. New insights into structural determinants of prion protein folding and stability.

    Science.gov (United States)

    Benetti, Federico; Legname, Giuseppe

    2015-01-01

    Prions are the etiological agent of fatal neurodegenerative diseases called prion diseases or transmissible spongiform encephalopathies. These maladies can be sporadic, genetic or infectious disorders. Prions are due to post-translational modifications of the cellular prion protein leading to the formation of a β-sheet enriched conformer with altered biochemical properties. The molecular events causing prion formation in sporadic prion diseases are still elusive. Recently, we published a research elucidating the contribution of major structural determinants and environmental factors in prion protein folding and stability. Our study highlighted the crucial role of octarepeats in stabilizing prion protein; the presence of a highly enthalpically stable intermediate state in prion-susceptible species; and the role of disulfide bridge in preserving native fold thus avoiding the misfolding to a β-sheet enriched isoform. Taking advantage from these findings, in this work we present new insights into structural determinants of prion protein folding and stability.

  4. Prion pathogenesis is faithfully reproduced in cerebellar organotypic slice cultures.

    Directory of Open Access Journals (Sweden)

    Jeppe Falsig

    Full Text Available Prions cause neurodegeneration in vivo, yet prion-infected cultured cells do not show cytotoxicity. This has hampered mechanistic studies of prion-induced neurodegeneration. Here we report that prion-infected cultured organotypic cerebellar slices (COCS experienced progressive spongiform neurodegeneration closely reproducing prion disease, with three different prion strains giving rise to three distinct patterns of prion protein deposition. Neurodegeneration did not occur when PrP was genetically removed from neurons, and a comprehensive pharmacological screen indicated that neurodegeneration was abrogated by compounds known to antagonize prion replication. Prion infection of COCS and mice led to enhanced fodrin cleavage, suggesting the involvement of calpains or caspases in pathogenesis. Accordingly, neurotoxicity and fodrin cleavage were prevented by calpain inhibitors but not by caspase inhibitors, whereas prion replication proceeded unimpeded. Hence calpain inhibition can uncouple prion replication from its neurotoxic sequelae. These data validate COCS as a powerful model system that faithfully reproduces most morphological hallmarks of prion infections. The exquisite accessibility of COCS to pharmacological manipulations was instrumental in recognizing the role of calpains in neurotoxicity, and significantly extends the collection of tools necessary for rigorously dissecting prion pathogenesis.

  5. Prions: Beyond a Single Protein.

    Science.gov (United States)

    Das, Alvin S; Zou, Wen-Quan

    2016-07-01

    Since the term protein was first coined in 1838 and protein was discovered to be the essential component of fibrin and albumin, all cellular proteins were presumed to play beneficial roles in plants and mammals. However, in 1967, Griffith proposed that proteins could be infectious pathogens and postulated their involvement in scrapie, a universally fatal transmissible spongiform encephalopathy in goats and sheep. Nevertheless, this novel hypothesis had not been evidenced until 1982, when Prusiner and coworkers purified infectious particles from scrapie-infected hamster brains and demonstrated that they consisted of a specific protein that he called a "prion." Unprecedentedly, the infectious prion pathogen is actually derived from its endogenous cellular form in the central nervous system. Unlike other infectious agents, such as bacteria, viruses, and fungi, prions do not contain genetic materials such as DNA or RNA. The unique traits and genetic information of prions are believed to be encoded within the conformational structure and posttranslational modifications of the proteins. Remarkably, prion-like behavior has been recently observed in other cellular proteins-not only in pathogenic roles but also serving physiological functions. The significance of these fascinating developments in prion biology is far beyond the scope of a single cellular protein and its related disease. PMID:27226089

  6. Amyloidosis, synucleinopathy, and prion encephalopathy in a neuropathic lysosomal storage disease: the CNS-biomarker potential of peripheral blood.

    Directory of Open Access Journals (Sweden)

    Bartholomew J Naughton

    Full Text Available Mucopolysaccharidosis (MPS IIIB is a devastating neuropathic lysosomal storage disease with complex pathology. This study identifies molecular signatures in peripheral blood that may be relevant to MPS IIIB pathogenesis using a mouse model. Genome-wide gene expression microarrays on pooled RNAs showed dysregulation of 2,802 transcripts in blood from MPS IIIB mice, reflecting pathological complexity of MPS IIIB, encompassing virtually all previously reported and as yet unexplored disease aspects. Importantly, many of the dysregulated genes are reported to be tissue-specific. Further analyses of multiple genes linked to major pathways of neurodegeneration demonstrated a strong brain-blood correlation in amyloidosis and synucleinopathy in MPS IIIB. We also detected prion protein (Prnp deposition in the CNS and Prnp dysregulation in the blood in MPS IIIB mice, suggesting the involvement of Prnp aggregation in neuropathology. Systemic delivery of trans-BBB-neurotropic rAAV9-hNAGLU vector mediated not only efficient restoration of functional α-N-acetylglucosaminidase and clearance of lysosomal storage pathology in the central nervous system (CNS and periphery, but also the correction of impaired neurodegenerative molecular pathways in the brain and blood. Our data suggest that molecular changes in blood may reflect pathological status in the CNS and provide a useful tool for identifying potential CNS-specific biomarkers for MPS IIIB and possibly other neurological diseases.

  7. Increased Infectivity of Anchorless Mouse Scrapie Prions in Transgenic Mice Overexpressing Human Prion Protein

    OpenAIRE

    Race, Brent; Phillips, Katie; Meade-White, Kimberly; Striebel, James; Chesebro, Bruce

    2015-01-01

    Prion protein (PrP) is found in all mammals, mostly as a glycoprotein anchored to the plasma membrane by a C-terminal glycosylphosphatidylinositol (GPI) linkage. Following prion infection, host protease-sensitive prion protein (PrPsen or PrPC) is converted into an abnormal, disease-associated, protease-resistant form (PrPres). Biochemical characteristics, such as the PrP amino acid sequence, and posttranslational modifications, such as glycosylation and GPI anchoring, can affect the transmiss...

  8. [Wilson's disease: clinical spectrum of liver disease].

    Science.gov (United States)

    Ochoa Palominos, Alejandra; Ibáñez Samaniego, Luis; Catalina Rodríguez, María-Vega; Pajares Díaz, José; Clemente Ricote, Gerardo

    2013-02-01

    Wilson's disease is a hereditary autosomal recessive disorder of copper metabolism,characterized by copper accumulation in the liver and brain. This rare entity, which has a broad clinical spectrum, is often difficult to diagnose and should therefore always be suspected in patients with liver disease of unclear cause. We describe two types of manifestation of liver disease in two patients; the first developed fulminant hepatic failure requiring urgent liver transplantation and the second showed advanced chronic liver disease and received standard medical treatment. The objective of this clinical observation is to analyze the diagnosis of Wilson's disease in two patients with distinct onset, illustrating the broad clinical spectrum of the disease, and its treatment.

  9. 微小 RNA 在朊病毒病等神经退行性疾病中的研究进展%Current research progress on microRNAs in neurodegenerative diseases including prion diseases

    Institute of Scientific and Technical Information of China (English)

    魏静; 高晨

    2016-01-01

    朊病毒病是一类具有传染性、不可逆且致命的神经退行性疾病,其致病机制为体内正常编码的细胞型朊蛋白(cellular prion protein ,PrPC )构象发生变化,形成了具有感染性的异常痒病型朊病毒(scrapie prion protein ,PrPSc ),但具体机制不清楚,目前为止尚无有效治疗方法。微小 RNA(microRNA ,miRNA)可在转录水平调控细胞蛋白表达,对神经系统发育及功能起重要作用。近年来,对一些特定miRNA在朊病毒病中相应调控机制、自发免疫、炎症信号转导及靶基因预测方面的研究可为治疗朊病毒病提供新的角度。本文就miRNA在朊病毒病发生中的相关研究进展进行综述,并详细探讨其中研究较为深入的miRNA。%Transmissible spongiform encephalopathies (TSEs) ,or prion diseases ,are irreversible and fatal neurodegenerative disorders associated with the conformational conversion of cellular prion protein (PrPC ) , a normal cellular protein ,into scrapie prion protein (PrPSc ) ,a structural isoform that is infectious and with no effective treatment yet .MicroRNA can regulate cellular protein expression at transcriptional level and may play an critical role in the development process of central nervous system .Recent studies indicate that some specific microRNAs involved in the regulation of innate immune response and inflammation signaling pathways may also be implicated in prion diseases and provide some new insights into the treatment of prion diseases .This review highlights the progress on microRNAs in the occurrence of prion diseases and discusses the leading microRNAs in detail .

  10. Encephalopathy for prions

    International Nuclear Information System (INIS)

    The encephalopathy spongyform for prions are neuro degenerative illness that can be sporadic or transferable, for infectious or hereditary mechanisms. Their investigation has outlined enormous challenges and in the historical journey in search of its cause two doctors have received the Nobel prize of medicine Carleton Gajdusek, for its works in New Guinea where it described the infectious transmission for cannibalistic rites that it took to studies of experimental transmission in chimpanzees and to its theory of the slow virus; later on, Stanley Prusiner developed its experimental works in hamsters, throwing to the neurobiology the prion concept (particles infectious proteinaceous not viral). The paper narrates the history of a patient that died in the San Juan de Dios of Bogota Hospital by cause of this prionic illness and clinical and pathological aspects are discussed

  11. Protease-sensitive prion species in neoplastic spleens of prion-infected mice with uncoupling of PrP(Sc) and prion infectivity.

    Science.gov (United States)

    Krasemann, Susanne; Neumann, Melanie; Szalay, Beata; Stocking, Carol; Glatzel, Markus

    2013-02-01

    Prion diseases are fatal neurodegenerative disorders. An important step in disease pathophysiology is the conversion of cellular prion protein (PrP(C)) to disease-associated misfolded conformers (PrP(Sc)). These misfolded PrP variants are a common component of prion infectivity and are detectable in diseased brain and lymphoreticular organs such as spleen. In the latter, PrP(Sc) is thought to replicate mainly in follicular dendritic cells within spleen follicles. Although the presence of PrP(Sc) is a hallmark for prion disease and serves as a main diagnostic criterion, in certain instances the amount of PrP(Sc) does not correlate well with neurotoxicity or prion infectivity. Therefore, it has been proposed that prions might be a mixture of different conformers and aggregates with differing properties. This study investigated the impact of disruption of spleen architecture by neoplasia on the abundance of different PrP species in spleens of prion-infected mice. Although follicular integrity was completely disturbed, titres of prion infectivity in neoplastic spleens were not significantly altered, yet no protease-resistant PrP(Sc) was detectable. Instead, unique protease-sensitive prion species could be detected in neoplastic spleens. These results indicate the dissociation of PrP(Sc) and prion infectivity and showed the presence of non-PrP(Sc) PrP species in spleen with divergent biochemical properties that become apparent after tissue architecture disruption. PMID:23136363

  12. Grass Plants Bind, Retain, Uptake, and Transport Infectious Prions

    Directory of Open Access Journals (Sweden)

    Sandra Pritzkow

    2015-05-01

    Full Text Available Prions are the protein-based infectious agents responsible for prion diseases. Environmental prion contamination has been implicated in disease transmission. Here, we analyzed the binding and retention of infectious prion protein (PrPSc to plants. Small quantities of PrPSc contained in diluted brain homogenate or in excretory materials (urine and feces can bind to wheat grass roots and leaves. Wild-type hamsters were efficiently infected by ingestion of prion-contaminated plants. The prion-plant interaction occurs with prions from diverse origins, including chronic wasting disease. Furthermore, leaves contaminated by spraying with a prion-containing preparation retained PrPSc for several weeks in the living plant. Finally, plants can uptake prions from contaminated soil and transport them to aerial parts of the plant (stem and leaves. These findings demonstrate that plants can efficiently bind infectious prions and act as carriers of infectivity, suggesting a possible role of environmental prion contamination in the horizontal transmission of the disease.

  13. Grass plants bind, retain, uptake, and transport infectious prions.

    Science.gov (United States)

    Pritzkow, Sandra; Morales, Rodrigo; Moda, Fabio; Khan, Uffaf; Telling, Glenn C; Hoover, Edward; Soto, Claudio

    2015-05-26

    Prions are the protein-based infectious agents responsible for prion diseases. Environmental prion contamination has been implicated in disease transmission. Here, we analyzed the binding and retention of infectious prion protein (PrP(Sc)) to plants. Small quantities of PrP(Sc) contained in diluted brain homogenate or in excretory materials (urine and feces) can bind to wheat grass roots and leaves. Wild-type hamsters were efficiently infected by ingestion of prion-contaminated plants. The prion-plant interaction occurs with prions from diverse origins, including chronic wasting disease. Furthermore, leaves contaminated by spraying with a prion-containing preparation retained PrP(Sc) for several weeks in the living plant. Finally, plants can uptake prions from contaminated soil and transport them to aerial parts of the plant (stem and leaves). These findings demonstrate that plants can efficiently bind infectious prions and act as carriers of infectivity, suggesting a possible role of environmental prion contamination in the horizontal transmission of the disease. PMID:25981035

  14. Grass plants bind, retain, uptake, and transport infectious prions.

    Science.gov (United States)

    Pritzkow, Sandra; Morales, Rodrigo; Moda, Fabio; Khan, Uffaf; Telling, Glenn C; Hoover, Edward; Soto, Claudio

    2015-05-26

    Prions are the protein-based infectious agents responsible for prion diseases. Environmental prion contamination has been implicated in disease transmission. Here, we analyzed the binding and retention of infectious prion protein (PrP(Sc)) to plants. Small quantities of PrP(Sc) contained in diluted brain homogenate or in excretory materials (urine and feces) can bind to wheat grass roots and leaves. Wild-type hamsters were efficiently infected by ingestion of prion-contaminated plants. The prion-plant interaction occurs with prions from diverse origins, including chronic wasting disease. Furthermore, leaves contaminated by spraying with a prion-containing preparation retained PrP(Sc) for several weeks in the living plant. Finally, plants can uptake prions from contaminated soil and transport them to aerial parts of the plant (stem and leaves). These findings demonstrate that plants can efficiently bind infectious prions and act as carriers of infectivity, suggesting a possible role of environmental prion contamination in the horizontal transmission of the disease.

  15. De novo generation of prion strains.

    Science.gov (United States)

    Colby, David W; Prusiner, Stanley B

    2011-11-01

    Prions are self-replicating proteins that can cause neurodegenerative disorders such as bovine spongiform encephalopathy (also known as mad cow disease). Aberrant conformations of prion proteins accumulate in the central nervous system, causing spongiform changes in the brain and eventually death. Since the inception of the prion hypothesis - which states that misfolded proteins are the infectious agents that cause these diseases - researchers have sought to generate infectious proteins from defined components in the laboratory with varying degrees of success. Here, we discuss several recent studies that have produced an array of novel prion strains in vitro that exhibit increasingly high titres of infectivity. These advances promise unprecedented insight into the structure of prions and the mechanisms by which they originate and propagate. PMID:21947062

  16. Roles of methionine oxidation in E200K prion protein misfolding: Implications for the mechanism of pathogenesis in E200K linked familial Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Wang, Zonglin; Feng, Boya; Xiao, Gengfu; Zhou, Zheng

    2016-04-01

    Prion diseases are a group of neurodegenerative diseases caused by prion protein (PrP) conformational changes. More than 30 PRNP gene mutations have been associated with familial prion diseases. E200K-associated familial Creutzfeldt-Jakob disease (fCJD) is the most common inherited prion disease. One of the hallmarks of prion diseases is the accumulation of oxidative damage. The mechanism by which oxidative modification of methionine (Met) residues influence the E200K PrP misfolding remains unclear. Here, we examined the stability, structural change, oligomerization and proteinase K resistance of unoxidized/oxidized E200K PrP and Met-to-Leu mutants. We found that oxidation of surface-exposed Met109/112/129/134/154/166 residues significantly destabilized E200K PrP but had a limited impact on the protein's structure. The oxidation of Met213 was the initial step in the conformational conversion of E200K PrP and facilitated the further oxidation of Met205/206. The oxidation of Met213/205/206 led to the exposure of the inner hydrophobic core, disrupted the overall structure of E200K PrP and induced the formation of large soluble multimers at low pH. In addition, the aggregation behavior of oxidized E200K PrP at the cellular level was investigated using E200K PrP Met-to-Ser mutants. The results showed that M109/112/129/154S or M134/166S mutants were efficiently localized on the cell membrane, whereas the M213/205/206S mutant generated many of aggregated fluorescent dots in the cytoplasm. The present work provides important clues for understanding the special roles of methionine oxidation in E200K PrP misfolding and links oxidative stress and consequent misfolding of oxidative damaged E200K PrP with the pathogenic mechanism of E200K-associated fCJD.

  17. Roles of methionine oxidation in E200K prion protein misfolding: Implications for the mechanism of pathogenesis in E200K linked familial Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Wang, Zonglin; Feng, Boya; Xiao, Gengfu; Zhou, Zheng

    2016-04-01

    Prion diseases are a group of neurodegenerative diseases caused by prion protein (PrP) conformational changes. More than 30 PRNP gene mutations have been associated with familial prion diseases. E200K-associated familial Creutzfeldt-Jakob disease (fCJD) is the most common inherited prion disease. One of the hallmarks of prion diseases is the accumulation of oxidative damage. The mechanism by which oxidative modification of methionine (Met) residues influence the E200K PrP misfolding remains unclear. Here, we examined the stability, structural change, oligomerization and proteinase K resistance of unoxidized/oxidized E200K PrP and Met-to-Leu mutants. We found that oxidation of surface-exposed Met109/112/129/134/154/166 residues significantly destabilized E200K PrP but had a limited impact on the protein's structure. The oxidation of Met213 was the initial step in the conformational conversion of E200K PrP and facilitated the further oxidation of Met205/206. The oxidation of Met213/205/206 led to the exposure of the inner hydrophobic core, disrupted the overall structure of E200K PrP and induced the formation of large soluble multimers at low pH. In addition, the aggregation behavior of oxidized E200K PrP at the cellular level was investigated using E200K PrP Met-to-Ser mutants. The results showed that M109/112/129/154S or M134/166S mutants were efficiently localized on the cell membrane, whereas the M213/205/206S mutant generated many of aggregated fluorescent dots in the cytoplasm. The present work provides important clues for understanding the special roles of methionine oxidation in E200K PrP misfolding and links oxidative stress and consequent misfolding of oxidative damaged E200K PrP with the pathogenic mechanism of E200K-associated fCJD. PMID:26779934

  18. Coexistence of two forms of disease-associated prion protein in extracerebral tissues of cattle infected with H-type bovine spongiform encephalopathy.

    Science.gov (United States)

    Okada, Hiroyuki; Miyazawa, Kohtaro; Masujin, Kentaro; Yokoyama, Takashi

    2016-08-01

    H-type bovine spongiform encephalopathy (H-BSE) is an atypical form of BSE in aged cattle. H-BSE is characterized by the presence of two proteinase K-resistant forms of disease-associated prion protein (PrP(Sc)), identified as PrP(Sc) #1 and PrP(Sc) #2, in the brain. To investigate the coexistence of different PrP(Sc) forms in the extracerebral tissues of cattle experimentally infected with H-BSE, immunohistochemical and molecular analyses were performed by using N-terminal-, core-region- and C-terminal-specific anti-prion protein antibodies. Our results demonstrated that two distinct forms of PrP(Sc) coexisted in the various extracerebral tissues. PMID:27010466

  19. Affinity Association Between Polynucleotide, Glycoprotein, or Sulfated Polysaccharides and Disease-Associated Prion Protein

    Directory of Open Access Journals (Sweden)

    Kazuo Tsukui

    2009-01-01

    Full Text Available Proteinase-K resistant prion protein (PrPres has the property to aggregate in TSE-injured animal tissues. We have developed a test method to discriminate scrapie-infected and mock-infected hamsters by detecting the PrPres in plasma. It seemed that aggregation of the PrPres with some heterogeneous molecule(s enabled successful detection by this method. In order to investigate which molecule became the partner in the PrPres aggregates; we examined some molecules that could presumably have this ability. As a result, we found synthetic Poly-A RNA, especially in its denatured form, to be the most effective entity although glycoprotein, sulfated polysaccharide showed less effectiveness. DNA in the denatured form also has a high affinity, although in the presence of protein the effectiveness unsuccessful. On the basis of this result, it is possible that the PrPres aggregate in scrapie-infected hamster plasma is composed of PrPres and RNA.

  20. Direct detection of soil-bound prions.

    Directory of Open Access Journals (Sweden)

    Sacha Genovesi

    Full Text Available Scrapie and chronic wasting disease are contagious prion diseases affecting sheep and cervids, respectively. Studies have indicated that horizontal transmission is important in sustaining these epidemics, and that environmental contamination plays an important role in this. In the perspective of detecting prions in soil samples from the field by more direct methods than animal-based bioassays, we have developed a novel immuno-based approach that visualises in situ the major component (PrP(Sc of prions sorbed onto agricultural soil particles. Importantly, the protocol needs no extraction of the protein from soil. Using a cell-based assay of infectivity, we also report that samples of agricultural soil, or quartz sand, acquire prion infectivity after exposure to whole brain homogenates from prion-infected mice. Our data provide further support to the notion that prion-exposed soils retain infectivity, as recently determined in Syrian hamsters intracerebrally or orally challenged with contaminated soils. The cell approach of the potential infectivity of contaminated soil is faster and cheaper than classical animal-based bioassays. Although it suffers from limitations, e.g. it can currently test only a few mouse prion strains, the cell model can nevertheless be applied in its present form to understand how soil composition influences infectivity, and to test prion-inactivating procedures.

  1. De novo generation of infectious prions with bacterially expressed recombinant prion protein.

    Science.gov (United States)

    Zhang, Zhihong; Zhang, Yi; Wang, Fei; Wang, Xinhe; Xu, Yuanyuan; Yang, Huaiyi; Yu, Guohua; Yuan, Chonggang; Ma, Jiyan

    2013-12-01

    The prion hypothesis is strongly supported by the fact that prion infectivity and the pathogenic conformer of prion protein (PrP) are simultaneously propagated in vitro by the serial protein misfolding cyclic amplification (sPMCA). However, due to sPMCA's enormous amplification power, whether an infectious prion can be formed de novo with bacterially expressed recombinant PrP (rPrP) remains to be satisfactorily resolved. To address this question, we performed unseeded sPMCA with rPrP in a laboratory that has never been exposed to any native prions. Two types of proteinase K (PK)-resistant and self-perpetuating recombinant PrP conformers (rPrP-res) with PK-resistant cores of 17 or 14 kDa were generated. A bioassay revealed that rPrP-res(17kDa) was highly infectious, causing prion disease in wild-type mice with an average survival time of about 172 d. In contrast, rPrP-res(14kDa) completely failed to induce any disease. Our findings reveal that sPMCA is sufficient to initiate various self-perpetuating PK-resistant rPrP conformers, but not all of them possess in vivo infectivity. Moreover, generating an infectious prion in a prion-free environment establishes that an infectious prion can be formed de novo with bacterially expressed rPrP.

  2. Lactoferrin from bovine colostrum regulates prolyl hydroxylase 2 activity and prevents prion protein-mediated neuronal cell damage via cellular prion protein.

    Science.gov (United States)

    Park, Y-G; Moon, J-H; Park, S-Y

    2014-08-22

    Prion disorders are associated with the conversion of normal cellular prion protein (PrPc) to the abnormal scrapie isoform of prion protein (PrPsc). Recent studies have shown that expression of normal PrPc is regulated by hypoxia-inducible factor-1 alpha (HIF-1α), and that lactoferrin increases full-length PrPc on the cell surface. Lactoferrin is an 80-kDa iron-binding glycoprotein with various biological activities, including iron-chelating ability. HIF-1α and the associated ubiquitin-proteasome pathway are regulated by HIF prolyl-hydroxylases 2 (PHD2). We hypothesized that lactoferrin regulates PHD2 expression and enzymatic activity, and the PHD2 regulation promotes HIF-1α stability and prevention of neuronal cell death mediated by prion protein (PrP) residues (106-126). Lactoferrin prevented PrP (106-126)-induced neurotoxicity by the induction of PrPc expression via promoting HIF-1α stability in neuronal cells. Our results demonstrated that lactoferrin prevented PrP (106-126)-induced neurotoxicity via the up-regulation of HIF-1α stability determined by PHD2 expression and enzymatic activity. These findings suggest that possible therapies such as PHD2 inhibition, or promotion of lactoferrin secretion, may have clinical benefits in neurodegenerative diseases, including prion disease. PMID:24875174

  3. Prions: an evolutionary perspective.

    Science.gov (United States)

    Ogayar, A; Sánchez-Pérez, M

    1998-09-01

    Studies in both prion-due diseases in mammals and some non-Mendelian hereditary processes in yeasts have demonstrated that certain proteins are able to transmit structural information and self-replication. This induces the corresponding conformational changes in other proteins with identical or similar sequences. This ability of proteins may have been very useful during prebiotic chemical evolution, prior to the establishment of the genetic code. During this stage, proteins (proteinoids) must have molded and selected their structural folding units through direct interaction with the environment. The proteinoids that acquired the ability to propagate their conformations (which we refer to as conformons) would have acted as reservoirs and transmitters of a given structural information and hence could have acted as selectors for conformational changes. Despite the great advantage that arose from the establishment of the genetic code, the ability to propagate conformational changes did not necessarily disappear. Depending on the degree of involvement of this capacity in biological evolution, we propose two not mutually exclusive hypotheses: (i) extant prions could be an atavism of ancestral conformons, which would have co-evolved with cells, and (ii) the evolution of conformons would have produced cellular proteins, able to transmit structural information, and, in some cases, participating in certain processes of regulation and epigenesis. Therefore, prions could also be seen as conformons of a conventional infectious agent (or one that co-evolved with it independently) that, after a longer or shorter adaptive period, would have interacted with conformons from the host cells. PMID:10943358

  4. Heterologous cross-seeding mimics cross-species prion conversion in a yeast model

    Directory of Open Access Journals (Sweden)

    Liebman Susan W

    2009-05-01

    Full Text Available Abstract Background Prions are self-perpetuating, infectious, aggregated proteins that are associated with several neurodegenerative diseases in mammals and heritable traits in yeast. Sup35p, the protein determinant of the yeast prion [PSI+], has a conserved C terminal domain that performs the Sup35p function and a prion domain that is highly divergent. Prions formed by chimeras of the prion domain of various species fused to the C domain of Saccharomyces cerevisiae exhibit a 'species barrier', a phenomenon first observed in mammals, and often fail to transmit the prion state to chimeras with prion domains of other species. Results We focus on the chimera containing the prion domain of Pichia methanolica and examine how tight the 'species barrier' is between the chimera and S. cerevisiae. Although either of two Q/N-rich prions, [PSI+] or [PIN+], enhances the formation of the chimeric prion, [CHI+PM], neither a non-Q/N-rich prion nor a non-prion Q-rich aggregate promotes the formation of [CHI+PM]. [CHI+PM] has many features characteristic of yeast prions: aggregation, cytoplasmic transmission and a two-level protein structure. [CHI+PM] formed in the presence of [PSI+] can propagate independently of [PSI+] and forms at least two different variants of the prion, suggesting the generation and not transmission of new prion seeds. Conclusion Although the sequence similarity between the S. cerevisiae Q/N-rich prion determinants and the P. methanolica prion domain is low, we find that the chimera containing the prion domain of P. methanolica can occasionally be cross-seeded by [PSI+] to mimic crossing the species barrier, to form the [CHI+PM] prion. Our data suggests that crossing the barrier occurs by a de novo formation of the foreign chimeric prion. Thus, the species barrier appears to be crossed by a heterologous seeding mechanism, wherein the infected prion protein uses the pre-existing seed as an inefficient template.

  5. Prions Ex Vivo: What Cell Culture Models Tell Us about Infectious Proteins

    OpenAIRE

    Sybille Krauss; Ina Vorberg

    2013-01-01

    Prions are unconventional infectious agents that are composed of misfolded aggregated prion protein. Prions replicate their conformation by template-assisted conversion of the endogenous prion protein PrP. Templated conversion of soluble proteins into protein aggregates is also a hallmark of other neurodegenerative diseases. Alzheimer's disease or Parkinson's disease are not considered infectious diseases, although aggregate pathology appears to progress in a stereotypical fashion reminiscent...

  6. Age at Death of Creutzfeldt-Jakob disease in subsequent family generation carrying the E200K mutation of the prion protein gene.

    Directory of Open Access Journals (Sweden)

    Maurizio Pocchiari

    Full Text Available BACKGROUND: The E200K mutation of the prion protein gene (PRNP is the most frequent amino acid substitution in genetic Creutzfeldt-Jakob disease and is the only one responsible for the appearance of clustered cases in the world. In the Israel and Slovakian clusters, age of disease onset was reduced in successive generations but the absence of a clear molecular basis raised the possibility that this event was an observational bias. The aim of the present study was to investigate possible selection biases or confounding factors related to anticipation in E200K CJD patients belonging to a cluster in Southern Italy. METHODS: Clinical and demographical data of 41 parent-offspring pairs from 19 pedigrees of the Italian cluster of E200K patients were collected. Age at death of parents was compared with age at death of E200K CJD offspring. Subgroup analyses were performed for controlling possible selection biases, confounding factors, or both. RESULTS: The mean age at death/last follow-up of the parent generation was 71.4 years while that of CJD offspring was 59.3 years with an estimated anticipation of 12.1 years. When the same analysis was performed including only parents with CJD or carrying the E200K mutation (n = 26, the difference between offspring and parents increased to 14.8 years. CONCLUSIONS: These results show that early age at death occurs in offspring of families carrying the E200K PRNP mutation and that this event is not linked to observational biases. Although molecular or environmental bases for this occurrence remain unsettled, this information is important for improving the accuracy of information to give to mutated carriers.

  7. Recombinant Human Prion Protein Inhibits Prion Propagation in vitro

    OpenAIRE

    Jue Yuan; Yi-An Zhan; Romany Abskharon; Xiangzhu Xiao; Manuel Camacho Martinez; Xiaochen Zhou; Geoff Kneale; Jacqueline Mikol; Sylvain Lehmann; Surewicz, Witold K.; Joaquín Castilla; Jan Steyaert; Shulin Zhang; Qingzhong Kong; Petersen, Robert B.

    2013-01-01

    Prion diseases are associated with the conformational conversion of the cellular prion protein (PrPC) into the pathological scrapie isoform (PrPSc) in the brain. Both the in vivo and in vitro conversion of PrPC into PrPSc is significantly inhibited by differences in amino acid sequence between the two molecules. Using protein misfolding cyclic amplification (PMCA), we now report that the recombinant full-length human PrP (rHuPrP23-231) (that is unglycosylated and lacks the glycophosphatidylin...

  8. Effects of solution chemistry and aging time on prion protein adsorption and replication of soil-bound prions.

    Directory of Open Access Journals (Sweden)

    Samuel E Saunders

    Full Text Available Prion interactions with soil may play an important role in the transmission of chronic wasting disease (CWD and scrapie. Prions are known to bind to a wide range of soil surfaces, but the effects of adsorption solution chemistry and long-term soil binding on prion fate and transmission risk are unknown. We investigated HY TME prion protein (PrP(Sc adsorption to soil minerals in aqueous solutions of phosphate buffered saline (PBS, sodium chloride, calcium chloride, and deionized water using western blotting. The replication efficiency of bound prions following adsorption in these solutions was also evaluated by protein misfolding cyclic amplification (PMCA. Aging studies investigated PrP(Sc desorption and replication efficiency up to one year following adsorption in PBS or DI water. Results indicate that adsorption solution chemistry can affect subsequent prion replication or desorption ability, especially after incubation periods of 30 d or longer. Observed effects were minor over the short-term (7 d or less. Results of long-term aging experiments demonstrate that unbound prions or prions bound to a diverse range of soil surfaces can readily replicate after one year. Our results suggest that while prion-soil interactions can vary with solution chemistry, prions bound to soil could remain a risk for transmitting prion diseases after months in the environment.

  9. Anti-prion activity of Brilliant Blue G.

    Directory of Open Access Journals (Sweden)

    Yoshifumi Iwamaru

    Full Text Available BACKGROUND: Prion diseases are fatal neurodegenerative disorders with no effective therapy currently available. Accumulating evidence has implicated over-activation of P2X7 ionotropic purinergic receptor (P2X7R in the progression of neuronal loss in several neurodegenerative diseases. This has led to the speculation that simultaneous blockade of this receptor and prion replication can be an effective therapeutic strategy for prion diseases. We have focused on Brilliant Blue G (BBG, a well-known P2X7R antagonist, possessing a chemical structure expected to confer anti-prion activity and examined its inhibitory effect on the accumulation of pathogenic isoforms of prion protein (PrPres in a cellular and a mouse model of prion disease in order to determine its therapeutic potential. PRINCIPAL FINDINGS: BBG prevented PrPres accumulation in infected MG20 microglial and N2a neural cells at 50% inhibitory concentrations of 14.6 and 3.2 µM, respectively. Administration of BBG in vivo also reduced PrPres accumulation in the brains of mice with prion disease. However, it did not appear to alleviate the disease progression compared to the vehicle-treated controls, implying a complex role of P2X7R on the neuronal degeneration in prion diseases. SIGNIFICANCE: These results provide novel insights into the pathophysiology of prion diseases and have important implications for the treatment.

  10. Prions in dentistry: A need to be concerned and known.

    Science.gov (United States)

    Sushma, B; Gugwad, Sachin; Pavaskar, Rajdeep; Malik, Shambhvi A

    2016-01-01

    Prion diseases were first discovered by Stanley B. Prusiner who defined prions as infectious, transmissible proteinaceous particles that lack nucleic acid and are composed exclusively of a modified isoform of the noninfectious cellular prion protein (PrPC). These are incurable neurodegenerative conditions affecting both animals and humans. They may be sporadic, infectious or inherited in origin. Human prion diseases include Creutzfeldt-Jakob desease (CJD), Gerstmann- Straussler-Scheinker disease, Kuru and Fatal familial insomnia. Prions resist the conventional sterilization procedures and hence the dentists must be aware of such diseases so as to opt standard methods of infection control and decontamination for such infectious agents. This review article divulge the dentists with a brief overview of the characteristics of prions, the risk of transmission and the implications for infection control in dentist. PMID:27194872

  11. Strain Specific Resistance to Murine Scrapie Associated with a Naturally Occurring Human Prion Protein Polymorphism at Residue 171

    OpenAIRE

    Striebel, James F.; Race, Brent; Meade-White, Kimberly D.; LaCasse, Rachel; Chesebro, Bruce

    2011-01-01

    Transmissible spongiform encephalopathies (TSE) or prion diseases are neurodegenerative disorders associated with conversion of normal host prion protein (PrP) to a misfolded, protease-resistant form (PrPres). Genetic variations of prion protein in humans and animals can alter susceptibility to both familial and infectious prion diseases. The N171S PrP polymorphism is found mainly in humans of African descent, but its low incidence has precluded study of its possible influence on prion diseas...

  12. Strain specific resistance to murine scrapie associated with a naturally occurring human prion protein polymorphism at residue 171.

    OpenAIRE

    Striebel, James F.; Brent Race; Meade-White, Kimberly D.; Rachel LaCasse; Bruce Chesebro

    2011-01-01

    Transmissible spongiform encephalopathies (TSE) or prion diseases are neurodegenerative disorders associated with conversion of normal host prion protein (PrP) to a misfolded, protease-resistant form (PrPres). Genetic variations of prion protein in humans and animals can alter susceptibility to both familial and infectious prion diseases. The N171S PrP polymorphism is found mainly in humans of African descent, but its low incidence has precluded study of its possible influence on prion diseas...

  13. Epigenetic dominance of prion conformers.

    Directory of Open Access Journals (Sweden)

    Eri Saijo

    2013-10-01

    Full Text Available Although they share certain biological properties with nucleic acid based infectious agents, prions, the causative agents of invariably fatal, transmissible neurodegenerative disorders such as bovine spongiform encephalopathy, sheep scrapie, and human Creutzfeldt Jakob disease, propagate by conformational templating of host encoded proteins. Once thought to be unique to these diseases, this mechanism is now recognized as a ubiquitous means of information transfer in biological systems, including other protein misfolding disorders such as those causing Alzheimer's and Parkinson's diseases. To address the poorly understood mechanism by which host prion protein (PrP primary structures interact with distinct prion conformations to influence pathogenesis, we produced transgenic (Tg mice expressing different sheep scrapie susceptibility alleles, varying only at a single amino acid at PrP residue 136. Tg mice expressing ovine PrP with alanine (A at (OvPrP-A136 infected with SSBP/1 scrapie prions propagated a relatively stable (S prion conformation, which accumulated as punctate aggregates in the brain, and produced prolonged incubation times. In contrast, Tg mice expressing OvPrP with valine (V at 136 (OvPrP-V136 infected with the same prions developed disease rapidly, and the converted prion was comprised of an unstable (U, diffusely distributed conformer. Infected Tg mice co-expressing both alleles manifested properties consistent with the U conformer, suggesting a dominant effect resulting from exclusive conversion of OvPrP-V136 but not OvPrP-A136. Surprisingly, however, studies with monoclonal antibody (mAb PRC5, which discriminates OvPrP-A136 from OvPrP-V136, revealed substantial conversion of OvPrP-A136. Moreover, the resulting OvPrP-A136 prion acquired the characteristics of the U conformer. These results, substantiated by in vitro analyses, indicated that co-expression of OvPrP-V136 altered the conversion potential of OvPrP-A136 from the S to

  14. Expression mapping of tetracycline-responsive prion protein promoter: digital atlasing for generating cell-specific disease models.

    Science.gov (United States)

    Boy, Jana; Leergaard, Trygve B; Schmidt, Thorsten; Odeh, Francis; Bichelmeier, Ulrike; Nuber, Silke; Holzmann, Carsten; Wree, Andreas; Prusiner, Stanley B; Bujard, Hermann; Riess, Olaf; Bjaalie, Jan G

    2006-11-01

    We present a digital atlas system that allows mapping of molecular expression patterns at cellular resolution through large series of histological sections. Using this system, we have mapped the distribution of a distinct marker, encoded by the LacZ reporter gene driven by the tetracycline-responsive prion protein promoter in double transgenic mice. The purpose is to evaluate the suitability of this promoter mouse line for targeting genes of interest to specific brain regions, essential for construction of inducible transgenic disease models. Following processing to visualize the promoter expression, sections were counterstained to simultaneously display cytoarchitectonics. High-resolution mosaic images covering entire coronal sections were collected through the mouse brain at intervals of 200 microm. A web-based application provides access to a customized virtual microscopy tool for viewing and navigation within and across the section images. For each section image, the nearest section in a standard atlas is defined, and annotations of key structures and regions inserted. Putative categorization of labeled cells was performed with use of distribution patterns, followed by cell size and shape, as parameters that were compared to legacy data. Among the ensuing results were expression of this promoter in putative glial cells in the cerebellum (and not in Purkinje cells), in putative glial cells in the substantia nigra, in pallidal glial cells or interneurons, and in distinct cell layers and regions of the hippocampus. The study serves as a precursor for a database resource allowing evaluation of the suitability of different promoter mouse lines for generating disease models. PMID:16931059

  15. [Psychiatric manifestations by prions. A narrative review].

    Science.gov (United States)

    Carrillo Robles, Daniel; García Maldonado, Gerardo

    2016-01-01

    Prion diseases are a group of rare and rapidly progressive neurodegenerative conditions that may cause neuropsychiatric symptoms. This group of diseases has been described since the 18(th) century, but they were recognized decades later, when it became clear that the humans were affected by infected animals. There was controversy when the problem was attributed to a single protein with infective capacity. The common pathological process is characterized by the conversion of the normal cellular prion protein into an abnormal form. In humans, the illness has been classified as idiopathic, inherited and acquired through exposure to exogenous material containing abnormal prions. The most prominent neurological manifestation of prion diseases is the emergence of a rapidly progressive dementia, mioclonus associated with cerebellar ataxia and also extra pyramidal symptoms. Psychiatric symptoms occur in early stages of the illness and can contribute to timely diagnosis of this syndrome. Psychiatric symptoms have traditionally been grouped in three categories: affective symptoms, impaired motor function and psychotic symptoms. Such events usually occur during the prodromal period prior to the neurological manifestations and consists in the presence of social isolation, onset of delusions, irritability/aggression, visual hallucinations, anxiety and depression, and less frequent first-rank symptoms among others. Definite diagnosis requires post mortem examination. The possibility that a large number of cases may occur in the next years or that many cases have not been considered with this diagnosis is a fact. In our opinion, psychiatrists should be aware of symptoms of this disease. The main objective of this research consisted of assessing the correlation between this disturbance and neuro-psychiatric symptoms and particularly if this psychiatric manifestations integrate a clinical picture suggestive for the diagnosis of these diseases, but firstly reviewed taxonomic

  16. Prion infectivity detected in swine challenged with chronic wasting disease via the intracerebral or oral route

    Science.gov (United States)

    Chronic wasting disease (CWD) is a naturally-occurring, fatal neurodegenerative disease of North American cervids. The potential for swine to serve as a host for the agent of chronic wasting disease is unknown. In the US, feeding of ruminant by-products to ruminants is prohibited, but feeding of rum...

  17. Cell-biological aspects of the prion protein in transgenic Xenopus intermediate pituitary cells

    NARCIS (Netherlands)

    Rosmalen, J.W.G. van

    2007-01-01

    In mammals, prions are the causative agents of various neurodegenerative diseases (e.g. scrapie, mad cow and Creutzfeldt-Jakob disease) in which the three-dimensional structure of the normal cellular form of the prion protein (PrPC) is misfolded into the infectious scrapie form (PrPSc or prion). In

  18. Computational Studies of the Structural Stability of Rabbit Prion Protein Compared to Human and Mouse Prion Proteins

    CERN Document Server

    Zhang, Jiapu

    2011-01-01

    Prion diseases are invariably fatal and highly infectious neurodegenerative diseases affecting humans and animals. The neurodegenerative diseases such as Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob diseases, Gerstmann-Str$\\ddot{a}$ussler-Scheinker syndrome, Fatal Familial Insomnia, Kuru in humans, scrapie in sheep, bovine spongiform encephalopathy (or 'mad-cow' disease) and chronic wasting disease in cattle belong to prion diseases. By now there have not been some effective therapeutic approaches to treat all these prion diseases. Dogs, rabbits and horses were reported to be resistant to prion diseases. By the end of year 2010 all the NMR structures of dog, rabbit and horse prion proteins (X-ray for rabbits too) had been finished to release into protein data bank. Thus, at this moment it is very worth studying the NMR and X-ray molecular structures of horse, dog and rabbit prion proteins to obtain insights into their immunity prion diseases. The author found that dog and horse prion proteins have sta...

  19. Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains

    OpenAIRE

    Carroll, James A.; Striebel, James F.; Rangel, Alejandra; Woods, Tyson; Phillips, Katie; Peterson, Karin E.; Race, Brent; Chesebro, Bruce

    2016-01-01

    Misfolding and aggregation of host proteins are important features of the pathogenesis of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia and prion diseases. In all these diseases, the misfolded protein increases in amount by a mechanism involving seeded polymerization. In prion diseases, host prion protein is misfolded to form a pathogenic protease-resistant form, PrPSc, which accumulates in neurons, astroglia and microglia in the CNS. H...

  20. H-type bovine spongiform encephalopathy-complex molecular featrues and similarities with some human prion diseases

    NARCIS (Netherlands)

    Biacabe, A.G.; Jacobs, J.G.; Bencsik, A.; Langeveld, J.P.M.; Baron, T.G.M.

    2007-01-01

    We previously reported that some cattle affected by bovine spongiform encephalopathy (BSE) showed distinct molecular features of the protease-resistant prion protein (PrPres) in Western blot, with a 1-2 kDa higher apparent molecular mass of the unglycosylated PrPres associated with labelling by anti

  1. Accumulation of pathological prion protein PrPSc in the skin of animals with experimental and natural scrapie.

    Directory of Open Access Journals (Sweden)

    Achim Thomzig

    2007-05-01

    Full Text Available Prion infectivity and its molecular marker, the pathological prion protein PrP(Sc, accumulate in the central nervous system and often also in lymphoid tissue of animals or humans affected by transmissible spongiform encephalopathies. Recently, PrP(Sc was found in tissues previously considered not to be invaded by prions (e.g., skeletal muscles. Here, we address the question of whether prions target the skin and show widespread PrP(Sc deposition in this organ in hamsters perorally or parenterally challenged with scrapie. In hamsters fed with scrapie, PrP(Sc was detected before the onset of symptoms, but the bulk of skin-associated PrP(Sc accumulated in the clinical phase. PrP(Sc was localized in nerve fibres within the skin but not in keratinocytes, and the deposition of PrP(Sc in skin showed no dependence from the route of infection and lymphotropic dissemination. The data indicated a neurally mediated centrifugal spread of prions to the skin. Furthermore, in a follow-up study, we examined sheep naturally infected with scrapie and detected PrP(Sc by Western blotting in skin samples from two out of five animals. Our findings point to the skin as a potential reservoir of prions, which should be further investigated in relation to disease transmission.

  2. Curcumin Reduces Amyloid Fibrillation of Prion Protein and Decreases Reactive Oxidative Stress

    OpenAIRE

    Raymond Chung; Cheng-I Lee; Chi-Fen Lin; Cheng-Ping Jheng; Kun-Hua Yu

    2013-01-01

    Misfolding and aggregation into amyloids of the prion protein (PrP) is responsible for the development of fatal transmissible neurodegenerative diseases. Various studies on curcumin demonstrate promise for the prevention of Alzheimer’s disease and inhibition of PrPres accumulation. To evaluate the effect of curcumin on amyloid fibrillation of prion protein, we first investigated the effect of curcumin on mouse prion protein (mPrP) in a cell-free system. Curcumin reduced the prion fibril forma...

  3. Rapid Antemortem Detection of CWD Prions in Deer Saliva

    OpenAIRE

    Henderson, Davin M.; Matteo Manca; Nicholas J Haley; Denkers, Nathaniel D.; Nalls, Amy V.; Mathiason, Candace K.; Byron Caughey; Hoover, Edward A.

    2013-01-01

    Chronic wasting disease (CWD) is an efficiently transmitted prion disease of cervids, now identified in 22 United States, 2 Canadian provinces and Korea. One hallmark of CWD is the shedding of infectious prions in saliva, as demonstrated by bioassay in deer. It is also clear that the concentration of prions in saliva, blood, urine and feces is much lower than in the nervous system or lymphoid tissues. Rapid in vitro detection of CWD (and other) prions in body fluids and excreta has been probl...

  4. Clinic Analysis of Behcet Disease

    Institute of Scientific and Technical Information of China (English)

    Jingjun Lin; Hongni Li; Yixia Huang; Kangkeng Zheng; Zhongxia Zhou; Xiaofeng Lin

    2004-01-01

    Purpose: To analyze the clinic manifestation and prognosis of Behcet disease.Method: Twenty patients requiring inpatient treatment with Behcet disease were retrospectively analyzed.Results: The morbidity of Behcet disease is 5.5/100 000. In the systemic damage, stomatocace and skin lesion are 95%, eye lesion and genital ulcer 50%, joint lesion 45%,gastrointestinal lesion 35%, Uveitis is the major disease in eye lesion, and followed in order by retinal vasculitis and obstruction of retinal artery. Attack age average 30.3 years old. Diagnosis age average 34.8 years old. The patients stay in hospital for 41 days on the average. Cure rate is 55%, improvement rate 40%, blinding rate of eye lesion is 36%.Conclusions: Behcet disease is a multisystem lesion disease. Stomatocace and skin lesion is the major lesion, the next in common occurrence are eye and genital lesions. Repeated attack of uveitis, complicated cataract and secondary glaucoma are the major causes of blindness.

  5. Molecular Modeling of Prion Transmission to Humans

    Directory of Open Access Journals (Sweden)

    Etienne Levavasseur

    2014-10-01

    Full Text Available Using different prion strains, such as the variant Creutzfeldt-Jakob disease agent and the atypical bovine spongiform encephalopathy agents, and using transgenic mice expressing human or bovine prion protein, we assessed the reliability of protein misfolding cyclic amplification (PMCA to model interspecies and genetic barriers to prion transmission. We compared our PMCA results with in vivo transmission data characterized by attack rates, i.e., the percentage of inoculated mice that developed the disease. Using 19 seed/substrate combinations, we observed that a significant PMCA amplification was only obtained when the mouse line used as substrate is susceptible to the corresponding strain. Our results suggest that PMCA provides a useful tool to study genetic barriers to transmission and to study the zoonotic potential of emerging prion strains.

  6. 疯牛病毒蛋白自由基-大与小的结合%Prion radicals, a marriage between the big and the small

    Institute of Scientific and Technical Information of China (English)

    Chi Ming Yang

    1999-01-01

      When all the experimental evidence from prion research are reconciled, my interpretation of the available data argues that persuasive evidence suggests that putative forms of persistent sequence-specific prion radicals in transmissible spongiform encephalopathies (TSEs) can be responsible for the infectious agent. A mechanism corresponding to the self-replication of scrapie protein mediated by prion radicals is proposed. My analysis argues that prions replicate via a prion radical-mediated chain process and the generation of the prion radicals is associated with reactive oxidative species. All of the unusual nature of prion diseases in mammals can be explained by invokingthe prion protein radicals.

  7. Prion-like features of misfolded Aβ and tau aggregates.

    Science.gov (United States)

    Morales, Rodrigo; Callegari, Keri; Soto, Claudio

    2015-09-01

    Recent findings have shown that several misfolded proteins can transmit disease pathogenesis in a prion-like manner by transferring their conformational properties to normally folded units. However, the extent by which these molecule-to-molecule or cell-to-cell spreading processes reflect the entire prion behavior is now subject of controversy, especially due to the lack of epidemiological data supporting inter-individual transmission of non-prion protein misfolding diseases. Nevertheless, extensive research has shown that several of the typical characteristics of prions can be observed for Aβ and tau aggregates when administered in animal models. In this article we review recent studies describing the prion-like features of both proteins, highlighting the similarities with bona fide prions in terms of inter-individual transmission, their strain-like conformational diversity, and the transmission of misfolded aggregates by different routes of administration. PMID:25575736

  8. Generic amyloidogenicity of mammalian prion proteins from species susceptible and resistant to prions.

    Science.gov (United States)

    Nyström, Sofie; Hammarström, Per

    2015-01-01

    Prion diseases are lethal, infectious diseases associated with prion protein (PrP) misfolding. A large number of mammals are susceptible to both sporadic and acquired prion diseases. Although PrP is highly conserved and ubiquitously expressed in all mammals, not all species exhibit prion disease. By employing full length recombinant PrP from five known prion susceptible species (human, cattle, cat, mouse and hamster) and two species considered to be prion resistant (pig and dog) the amyloidogenicity of these PrPs has been delineated. All the mammalian PrPs, even from resistant species, were swiftly converted from the native state to amyloid-like structure when subjected to a native condition conversion assay. The PrPs displayed amyloidotypic tinctorial and ultrastructural hallmarks. Self-seeded conversion of the PrPs displayed significantly decreased lag phases demonstrating that nucleation dependent polymerization is a dominating mechanism in the fibrillation process. Fibrils from Aβ1-40, Aβ1-42, Lysozyme, Insulin and Transthyretin did not accelerate conversion of HuPrP whereas fibrils from HuPrP90-231 and HuPrP121-231 as well as full length PrPs of all PrPs efficiently seeded conversion showing specificity of the assay requiring the C-terminal PrP sequence. Our findings have implications for PrP misfolding and could have ramifications in the context of prion resistant species and silent carriers.

  9. Crossing species barrier by PrPSc replication in vitro generates new infectious prions

    OpenAIRE

    Castilla, Joaquín; Gonzalez-Romero, Dennisse; Saá, Paula; Morales, Rodrigo; Castro, Jorge; Soto, Claudio

    2008-01-01

    Prions are unconventional infectious agents composed exclusively by the misfolded prion protein (PrPSc), which transmits the disease by propagating its abnormal conformation to the cellular prion protein (PrPC). A key characteristic of prions is their species barrier, by which prions from one species can only infect a limited number of other species. Here we report the generation of novel infectious prions by inter-species transmission of PrPSc misfolding in vitro. Hamster PrPC misfolded by m...

  10. Computational Studies of the Structural Stability of Rabbit Prion Protein Compared to Human and Mouse Prion Proteins

    OpenAIRE

    Zhang, Jiapu

    2011-01-01

    Prion diseases are invariably fatal and highly infectious neurodegenerative diseases affecting humans and animals. The neurodegenerative diseases such as Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob diseases, Gerstmann-Str$\\ddot{a}$ussler-Scheinker syndrome, Fatal Familial Insomnia, Kuru in humans, scrapie in sheep, bovine spongiform encephalopathy (or 'mad-cow' disease) and chronic wasting disease in cattle belong to prion diseases. By now there have not been some effective therapeut...

  11. Trichinella infection and clinical disease

    DEFF Research Database (Denmark)

    Clausen, M R; Meyer, C N; Krantz, T;

    1996-01-01

    Trichinellosis is caused by ingestion of insufficiently cooked meat contaminated with infective larvae of Trichinella species. The clinical course is highly variable, ranging from no apparent infection to severe and even fatal disease. We report two illustrative cases of trichinellosis. Returning....... Life-threatening cardiopulmonary, renal and central nervous system complications developed. The patient recovered after several months. Her husband, who also ate the pork, did not have clinical symptoms, but an increased eosinophil count and a single larva in a muscle biopsy confirmed infection....... The epidemiology, clinical manifestations, diagnosis, treatment and prevention of trichinellosis are reviewed....

  12. Clinical stage of infection is critical in the antemortem diagnosis of chronic wasting disease in deer and elk

    Science.gov (United States)

    Chronic wasting disease (CWD) is an efficiently transmitted spongiform encephalopathy of cervids (e.g. deer, elk, and moose), and is the only known prion disease affecting both free-ranging wildlife and captive animals. The antemortem detection of CWD and other prion diseases has proven difficult, d...

  13. Prionic diseases

    Directory of Open Access Journals (Sweden)

    Abelardo Q-C Araujo

    2013-09-01

    Full Text Available Prion diseases are neurodegenerative illnesses due to the accumulation of small infectious pathogens containing protein but apparently lacking nucleic acid, which have long incubation periods and progress inexorably once clinical symptoms appear. Prions are uniquely resistant to a number of normal decontaminating procedures. The prionopathies [Kuru, Creutzfeldt-Jakob disease (CJD and its variants, Gerstmann-Sträussler-Scheinker (GSS syndrome and fatal familial insomnia (FFI] result from accumulation of abnormal isoforms of the prion protein in the brains of normal animals on both neuronal and non-neuronal cells. The accumulation of this protein or fragments of it in neurons leads to apoptosis and cell death. There is a strong link between mutations in the gene encoding the normal prion protein in humans (PRNP - located on the short arm of chromosome 20 – and forms of prion disease with a familial predisposition (familial CJD, GSS, FFI. Clinically a prionopathy should be suspected in any case of a fast progressing dementia with ataxia, myoclonus, or in individuals with pathological insomnia associated with dysautonomia. Magnetic resonance imaging, identification of the 14-3-3 protein in the cerebrospinal fluid, tonsil biopsy and genetic studies have been used for in vivo diagnosis circumventing the need of brain biopsy. Histopathology, however, remains the only conclusive method to reach a confident diagnosis. Unfortunately, despite numerous treatment efforts, prionopathies remain short-lasting and fatal diseases.

  14. Prion infection in cells is abolished by a mutated manganese transporter but shows no relation to zinc.

    Science.gov (United States)

    Pass, Rachel; Frudd, Karen; Barnett, James P; Blindauer, Claudia A; Brown, David R

    2015-09-01

    The cellular prion protein has been identified as a metalloprotein that binds copper. There have been some suggestions that prion protein also influences zinc and manganese homeostasis. In this study we used a series of cell lines to study the levels of zinc and manganese under different conditions. We overexpressed either the prion protein or known transporters for zinc and manganese to determine relations between the prion protein and both manganese and zinc homeostasis. Our observations supported neither a link between the prion protein and zinc metabolism nor any effect of altered zinc levels on prion protein expression or cellular infection with prions. In contrast we found that a gain of function mutant of a manganese transporter caused reduction of manganese levels in prion infected cells, loss of observable PrP(Sc) in cells and resistance to prion infection. These studies strengthen the link between manganese and prion disease.

  15. Chronic wasting disease and atypical forms of bovine spongiform encephalopathy and scrapie are not transmissible to mice expressing wild-type levels of human prion protein.

    Science.gov (United States)

    Wilson, Rona; Plinston, Chris; Hunter, Nora; Casalone, Cristina; Corona, Cristiano; Tagliavini, Fabrizio; Suardi, Silvia; Ruggerone, Margherita; Moda, Fabio; Graziano, Silvia; Sbriccoli, Marco; Cardone, Franco; Pocchiari, Maurizio; Ingrosso, Loredana; Baron, Thierry; Richt, Juergen; Andreoletti, Olivier; Simmons, Marion; Lockey, Richard; Manson, Jean C; Barron, Rona M

    2012-07-01

    The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several novel TSEs in sheep, cattle and deer have been described and the risk posed to humans by these agents is currently unknown. In this study, we inoculated two forms of atypical BSE (BASE and H-type BSE), a chronic wasting disease (CWD) isolate and seven isolates of atypical scrapie into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP). Upon challenge with these ruminant TSEs, gene-targeted Tg mice expressing human PrP did not show any signs of disease pathology. These data strongly suggest the presence of a substantial transmission barrier between these recently identified ruminant TSEs and humans. PMID:22495232

  16. Chronic wasting disease and atypical forms of bovine spongiform encephalopathy and scrapie are not transmissible to mice expressing wild-type levels of human prion protein.

    Science.gov (United States)

    Wilson, Rona; Plinston, Chris; Hunter, Nora; Casalone, Cristina; Corona, Cristiano; Tagliavini, Fabrizio; Suardi, Silvia; Ruggerone, Margherita; Moda, Fabio; Graziano, Silvia; Sbriccoli, Marco; Cardone, Franco; Pocchiari, Maurizio; Ingrosso, Loredana; Baron, Thierry; Richt, Juergen; Andreoletti, Olivier; Simmons, Marion; Lockey, Richard; Manson, Jean C; Barron, Rona M

    2012-07-01

    The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several novel TSEs in sheep, cattle and deer have been described and the risk posed to humans by these agents is currently unknown. In this study, we inoculated two forms of atypical BSE (BASE and H-type BSE), a chronic wasting disease (CWD) isolate and seven isolates of atypical scrapie into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP). Upon challenge with these ruminant TSEs, gene-targeted Tg mice expressing human PrP did not show any signs of disease pathology. These data strongly suggest the presence of a substantial transmission barrier between these recently identified ruminant TSEs and humans.

  17. Prion protein amyloidosis with divergent phenotype associated with two novel nonsense mutations in PRNP

    NARCIS (Netherlands)

    C. Jansen (Casper); P. Parchi (Piero); S. Capellari (Sabina); A.J. Vermeij (Ad); P. Corrado (Patrizia); F. Baas (Frank); R. Strammiello (Rosario); W.A. van Gool (Willem); J.C. van Swieten; A.J.M. Rozemuller (Annemieke)

    2010-01-01

    textabstractStop codon mutations in the gene encoding the prion protein (PRNP) are very rare and have thus far only been described in two patients with prion protein cerebral amyloid angiopathy (PrP-CAA). In this report, we describe the clinical, histopathological and pathological prion protein (PrP

  18. Live-cell FRET imaging reveals clustering of the prion protein at the cell surface induced by infectious prions.

    Science.gov (United States)

    Tavares, Evandro; Macedo, Joana A; Paulo, Pedro M R; Tavares, Catarina; Lopes, Carlos; Melo, Eduardo P

    2014-07-01

    Prion diseases are associated to the conversion of the prion protein into a misfolded pathological isoform. The mechanism of propagation of protein misfolding by protein templating remains largely unknown. Neuroblastoma cells were transfected with constructs of the prion protein fused to both CFP-GPI-anchored and to YFP-GPI-anchored and directed to its cell membrane location. Live-cell FRET imaging between the prion protein fused to CFP or YFP was measured giving consistent values of 10±2%. This result was confirmed by fluorescence lifetime imaging microscopy and indicates intermolecular interactions between neighbor prion proteins. In particular, considering that a maximum FRET efficiency of 17±2% was determined from a positive control consisting of a fusion CFP-YFP-GPI-anchored. A stable cell clone expressing the two fusions containing the prion protein was also selected to minimize cell-to-cell variability. In both, stable and transiently transfected cells, the FRET efficiency consistently increased in the presence of infectious prions - from 4±1% to 7±1% in the stable clone and from 10±2% to 16±1% in transiently transfected cells. These results clearly reflect an increased clustering of the prion protein on the membrane in the presence of infectious prions, which was not observed in negative control using constructs without the prion protein and upon addition of non-infected brain. Our data corroborates the recent view that the primary site for prion conversion is the cell membrane. Since our fluorescent cell clone is not susceptible to propagate infectivity, we hypothesize that the initial event of prion infectivity might be the clustering of the GPI-anchored prion protein.

  19. Soil clay content underlies prion infection odds

    Science.gov (United States)

    David, Walter W.; Walsh, D.P.; Farnsworth, Matthew L.; Winkelman, D.L.; Miller, M.W.

    2011-01-01

    Environmental factors-especially soil properties-have been suggested as potentially important in the transmission of infectious prion diseases. Because binding to montmorillonite (an aluminosilicate clay mineral) or clay-enriched soils had been shown to enhance experimental prion transmissibility, we hypothesized that prion transmission among mule deer might also be enhanced in ranges with relatively high soil clay content. In this study, we report apparent influences of soil clay content on the odds of prion infection in free-ranging deer. Analysis of data from prion-infected deer herds in northern Colorado, USA, revealed that a 1% increase in the clay-sized particle content in soils within the approximate home range of an individual deer increased its odds of infection by up to 8.9%. Our findings suggest that soil clay content and related environmental properties deserve greater attention in assessing risks of prion disease outbreaks and prospects for their control in both natural and production settings. ?? 2011 Macmillan Publishers Limited. All rights reserved.

  20. Patología del sueño en las enfermedades priónicas Sleep disorders in prion diseases

    Directory of Open Access Journals (Sweden)

    T. Ayuso

    2007-01-01

    Full Text Available Las enfermedades priónicas son un grupo de encefalopatías con cambios neurodegenerativos causados por una proteína alterada denominada prión cuyo dato característico es la transmisibilidad. Ocurren la mayoría de las veces de forma esporádica aunque un grupo de ellas son familiares asociadas a mutaciones en el gen de la proteína priónica. El polimorfismo genético parece determinar las diferentes variantes familiares. Una de las más enigmáticas e inhabituales es el Insomnio Letal Familiar (ILF, trastorno hereditario caracterizado por pérdida del sueño fisiológico con estupor onírico, hiperactividad autonómica y motora, y anomalías motoras. La polisomnografía de esta entidad refleja la incapacidad para producir un patrón fisiológico del sueño NREM y REM, así como de las fluctuaciones circadianas hormonales y vegetativas; la transición de vigilia a sueño está marcadamente alterada con desaparición precoz de los husos de sueño. La hipótesis del origen de estos trastornos es la pérdida neuronal talámica, especialmente en los núcleos anterior y dorsomedial, descrita en la neuropatología de estos pacientes; además la PET revela hipofunción de núcleos talámicos, centros responsables del control vigilia-sueño. En la enfermedad de Creutzfeldt-Jakob las alteraciones de sueño-vigilia no se han considerado características, no obstante, se han encontrado frecuentes alteraciones en los registros electroencefalográficos de sueño. Además de la neurodegeneración talámica puede haber mecanismos etiopatogénicos comunes en las enfermedades priónicas en relación con la función biológica de la proteína priónica.Prion diseases are a group of encephalopathies with neurodegenerative changes caused by an altered protein named prion whose characteristic datum is transmissibility. In most cases they occur in a sporadic form although a group of them are familial associated with mutations in the gene of the prion protein

  1. Efficient lymphoreticular prion propagation requires PrP(c) in stromal and hematopoietic cells.

    OpenAIRE

    Kaeser, P S; Klein, M A; Schwarz, P.; Aguzzi, A

    2001-01-01

    In most prion diseases, infectivity accumulates in lymphoreticular organs early after infection. Defects in hematopoietic compartments, such as impaired B-cell maturation, or in stromal compartments, such as abrogation of follicular dendritic cells, can delay or prevent lymphoreticular prion colonization. However, the nature of the compartment in which prion replication takes place is controversial, and it is unclear whether this compartment coincides with that expressing the normal prion pro...

  2. Efficient Lymphoreticular Prion Propagation Requires PrPc in Stromal and Hematopoietic Cells

    OpenAIRE

    Kaeser, Pascal S.; Klein, Michael A.; Schwarz, Petra; Aguzzi, Adriano

    2001-01-01

    In most prion diseases, infectivity accumulates in lymphoreticular organs early after infection. Defects in hematopoietic compartments, such as impaired B-cell maturation, or in stromal compartments, such as abrogation of follicular dendritic cells, can delay or prevent lymphoreticular prion colonization. However, the nature of the compartment in which prion replication takes place is controversial, and it is unclear whether this compartment coincides with that expressing the normal prion pro...

  3. Lymph nodal prion replication and neuroinvasion in mice devoid of follicular dendritic cells

    OpenAIRE

    Prinz, M.; Montrasio, F; Klein, M A; Schwarz, P.; Priller, J P; Odermatt, B; K. Pfeffer; Aguzzi, A

    2002-01-01

    Variant Creutzfeldt-Jakob disease and scrapie are typically initiated by extracerebral exposure to prions, and exhibit early prion accumulation in germinal centers. Follicular dendritic cells (FDCs), whose development and maintenance in germinal centers depends on tumor necrosis factor (TNF) and lymphotoxin (LT) signaling, are thought to be indispensable for extraneural prion pathogenesis. Here, we administered prions intraperitoneally to mice deficient for TNF and LT signaling components. LT...

  4. Role of the Lymphoreticular System in Prion Neuroinvasion from the Oral and Nasal Mucosa ▿

    OpenAIRE

    Bessen, Richard A.; Martinka, Scott; Kelly, Jessica; Gonzalez, Daniel

    2009-01-01

    Prion neuroinvasion from peripheral tissues involves agent replication in the lymphoreticular system (LRS) prior to entry into the nervous system. This study investigated the role of the LRS in prion neuroinvasion from the oral and nasal mucosa in wild-type and immunodeficient mice and in hamsters infected with the HY and DY strains of the transmissible mink encephalopathy (TME) agent. Following inoculation at neural sites, all hosts were susceptible to prion disease and had evidence of prion...

  5. Neuro degenerative diseases: clinical concerns

    International Nuclear Information System (INIS)

    Idiopathic Parkinson's disease (PD) and Alzheimer's disease (AD) are the main neuro-degenerative diseases (NDDs) seen clinically. They share some common clinical symptoms and neuro-pathological findings. The increase of life expectancy in the developed countries will inevitably contribute to enhance the prevalence of these diseases. Behavioral disorders, common in NDDs, will produce major care management challenges. Idiopathic Parkinson's disease corresponds to a histopathological diagnosis, based on the observation of a de-pigmentation and a neuronal loss in the substantia nigra, as well as on the presence of intra-neuronal inclusion bodies. AD is insidious with slowly progressive dementia in which the decline in memory constitutes the main complaint. The diagnosis of definite AD requires the presence of clinical criteria as well as the histopathological confirmation of brain lesions. The two main lesions are the presence of senile plaques and neuro-fibrillary tangles. Positron emission tomography (PET) explores cerebral metabolism and neurotransmitter kinetics in NDDs using principally [18F]-deoxyglucose and [18F]-dopa. Nigrostriatal dopaminergic function is altered in PD, as evidenced by the low uptake of [18F]-dopa in the posterior putamen as compared to anterior putamen and caudate nucleus. In contrast, [18F]-dopa uptake is equally depressed in all striatal structures in progressive supra-nuclear palsy. Regional glucose metabolism at rest is preserved in elderly once cerebral atrophy is taken into account. On the contrary, glucose metabolism is globally reduced in AD, with marked decrease in the parietal and temporal regions. PET has proved to be useful to study in vivo neurochemical processes in patients suffering from NDDs. The potential of this approach is still largely unexploited, and depends on new ligand production to establish early diagnosis and treatment follow-up. (author)

  6. Follicular dendritic cell-specific prion protein (PrP) expression alone is sufficient to sustain prion infection in the spleen.

    OpenAIRE

    Laura McCulloch; Brown, Karen L.; Bradford, Barry M.; John Hopkins; Mick Bailey; Klaus Rajewsky; Manson, Jean C; Mabbott, Neil A.

    2011-01-01

    Prion diseases are characterised by the accumulation of PrP(Sc), an abnormally folded isoform of the cellular prion protein (PrP(C)), in affected tissues. Following peripheral exposure high levels of prion-specific PrP(Sc) accumulate first upon follicular dendritic cells (FDC) in lymphoid tissues before spreading to the CNS. Expression of PrP(C) is mandatory for cells to sustain prion infection and FDC appear to express high levels. However, whether FDC actively replicate prions or simply acq...

  7. Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains

    Science.gov (United States)

    Carroll, James A.; Striebel, James F.; Rangel, Alejandra; Woods, Tyson; Phillips, Katie; Peterson, Karin E.; Race, Brent; Chesebro, Bruce

    2016-01-01

    Misfolding and aggregation of host proteins are important features of the pathogenesis of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia and prion diseases. In all these diseases, the misfolded protein increases in amount by a mechanism involving seeded polymerization. In prion diseases, host prion protein is misfolded to form a pathogenic protease-resistant form, PrPSc, which accumulates in neurons, astroglia and microglia in the CNS. Here using dual-staining immunohistochemistry, we compared the cell specificity of PrPSc accumulation at early preclinical times post-infection using three mouse scrapie strains that differ in brain regional pathology. PrPSc from each strain had a different pattern of cell specificity. Strain 22L was mainly associated with astroglia, whereas strain ME7 was mainly associated with neurons and neuropil. In thalamus and cortex, strain RML was similar to 22L, but in substantia nigra, RML was similar to ME7. Expression of 90 genes involved in neuroinflammation was studied quantitatively using mRNA from thalamus at preclinical times. Surprisingly, despite the cellular differences in PrPSc accumulation, the pattern of upregulated genes was similar for all three strains, and the small differences observed correlated with variations in the early disease tempo. Gene upregulation correlated with activation of both astroglia and microglia detected in early disease prior to vacuolar pathology or clinical signs. Interestingly, the profile of upregulated genes in scrapie differed markedly from that seen in two acute viral CNS diseases (LaCrosse virus and BE polytropic Friend retrovirus) that had reactive gliosis at levels similar to our prion-infected mice. PMID:27046083

  8. Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains.

    Science.gov (United States)

    Carroll, James A; Striebel, James F; Rangel, Alejandra; Woods, Tyson; Phillips, Katie; Peterson, Karin E; Race, Brent; Chesebro, Bruce

    2016-04-01

    Misfolding and aggregation of host proteins are important features of the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, frontotemporal dementia and prion diseases. In all these diseases, the misfolded protein increases in amount by a mechanism involving seeded polymerization. In prion diseases, host prion protein is misfolded to form a pathogenic protease-resistant form, PrPSc, which accumulates in neurons, astroglia and microglia in the CNS. Here using dual-staining immunohistochemistry, we compared the cell specificity of PrPSc accumulation at early preclinical times post-infection using three mouse scrapie strains that differ in brain regional pathology. PrPSc from each strain had a different pattern of cell specificity. Strain 22L was mainly associated with astroglia, whereas strain ME7 was mainly associated with neurons and neuropil. In thalamus and cortex, strain RML was similar to 22L, but in substantia nigra, RML was similar to ME7. Expression of 90 genes involved in neuroinflammation was studied quantitatively using mRNA from thalamus at preclinical times. Surprisingly, despite the cellular differences in PrPSc accumulation, the pattern of upregulated genes was similar for all three strains, and the small differences observed correlated with variations in the early disease tempo. Gene upregulation correlated with activation of both astroglia and microglia detected in early disease prior to vacuolar pathology or clinical signs. Interestingly, the profile of upregulated genes in scrapie differed markedly from that seen in two acute viral CNS diseases (LaCrosse virus and BE polytropic Friend retrovirus) that had reactive gliosis at levels similar to our prion-infected mice. PMID:27046083

  9. Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains.

    Directory of Open Access Journals (Sweden)

    James A Carroll

    2016-04-01

    Full Text Available Misfolding and aggregation of host proteins are important features of the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, frontotemporal dementia and prion diseases. In all these diseases, the misfolded protein increases in amount by a mechanism involving seeded polymerization. In prion diseases, host prion protein is misfolded to form a pathogenic protease-resistant form, PrPSc, which accumulates in neurons, astroglia and microglia in the CNS. Here using dual-staining immunohistochemistry, we compared the cell specificity of PrPSc accumulation at early preclinical times post-infection using three mouse scrapie strains that differ in brain regional pathology. PrPSc from each strain had a different pattern of cell specificity. Strain 22L was mainly associated with astroglia, whereas strain ME7 was mainly associated with neurons and neuropil. In thalamus and cortex, strain RML was similar to 22L, but in substantia nigra, RML was similar to ME7. Expression of 90 genes involved in neuroinflammation was studied quantitatively using mRNA from thalamus at preclinical times. Surprisingly, despite the cellular differences in PrPSc accumulation, the pattern of upregulated genes was similar for all three strains, and the small differences observed correlated with variations in the early disease tempo. Gene upregulation correlated with activation of both astroglia and microglia detected in early disease prior to vacuolar pathology or clinical signs. Interestingly, the profile of upregulated genes in scrapie differed markedly from that seen in two acute viral CNS diseases (LaCrosse virus and BE polytropic Friend retrovirus that had reactive gliosis at levels similar to our prion-infected mice.

  10. What Makes a Protein Sequence a Prion?

    Science.gov (United States)

    Sabate, Raimon; Rousseau, Frederic; Schymkowitz, Joost; Ventura, Salvador

    2015-01-01

    Typical amyloid diseases such as Alzheimer's and Parkinson's were thought to exclusively result from de novo aggregation, but recently it was shown that amyloids formed in one cell can cross-seed aggregation in other cells, following a prion-like mechanism. Despite the large experimental effort devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the primary sequence. In many cases, prion structural conversion is driven by the presence of relatively large glutamine/asparagine (Q/N) enriched segments. Several studies suggest that it is the amino acid composition of these regions rather than their specific sequence that accounts for their priogenicity. However, our analysis indicates that it is instead the presence and potency of specific short amyloid-prone sequences that occur within intrinsically disordered Q/N-rich regions that determine their prion behaviour, modulated by the structural and compositional context. This provides a basis for the accurate identification and evaluation of prion candidate sequences in proteomes in the context of a unified framework for amyloid formation and prion propagation. PMID:25569335

  11. Mutability of prions

    OpenAIRE

    Li, Jiali; Mahal, Sukhvir P.; Demczyk, Cheryl A.; Weissmann, Charles

    2011-01-01

    Murine prions transferred from brain to cultured cells gradually adapt to the new environment. Brain-derived 22L prions can infect neuroblastoma-derived PK1 cells in the presence of swainsonine (swa); that is, they are ‘swa resistant'. PK1 cell-adapted 22L prions are swa sensitive; however, propagation in swa results in selection of swa-resistant substrains. Cloned, PK1 cell-adapted 22L prions were initially unable to develop swa resistance (‘swa incompetent'); however, after serial propagati...

  12. Huntington's disease: a clinical review

    Directory of Open Access Journals (Sweden)

    Roos Raymund AC

    2010-12-01

    Full Text Available Abstract Huntington disease (HD is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia. Prevalence in the Caucasian population is estimated at 1/10,000-1/20,000. Mean age at onset of symptoms is 30-50 years. In some cases symptoms start before the age of 20 years with behavior disturbances and learning difficulties at school (Juvenile Huntington's disease; JHD. The classic sign is chorea that gradually spreads to all muscles. All psychomotor processes become severely retarded. Patients experience psychiatric symptoms and cognitive decline. HD is an autosomal dominant inherited disease caused by an elongated CAG repeat (36 repeats or more on the short arm of chromosome 4p16.3 in the Huntingtine gene. The longer the CAG repeat, the earlier the onset of disease. In cases of JHD the repeat often exceeds 55. Diagnosis is based on clinical symptoms and signs in an individual with a parent with proven HD, and is confirmed by DNA determination. Pre-manifest diagnosis should only be performed by multidisciplinary teams in healthy at-risk adult individuals who want to know whether they carry the mutation or not. Differential diagnoses include other causes of chorea including general internal disorders or iatrogenic disorders. Phenocopies (clinically diagnosed cases of HD without the genetic mutation are observed. Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis. Preimplantation diagnosis with in vitro fertilization is offered in several countries. There is no cure. Management should be multidisciplinary and is based on treating symptoms with a view to improving quality of life. Chorea is treated with dopamine receptor blocking or depleting agents. Medication and non-medical care for depression and aggressive behavior may be required. The progression of the disease leads to a complete dependency in daily life, which

  13. Lions and prions and deer demise.

    Directory of Open Access Journals (Sweden)

    Michael W Miller

    Full Text Available BACKGROUND: Contagious prion diseases--scrapie of sheep and chronic wasting disease of several species in the deer family--give rise to epidemics that seem capable of compromising host population viability. Despite this prospect, the ecological consequences of prion disease epidemics in natural populations have received little consideration. METHODOLOGY/PRINCIPAL FINDINGS: Using a cohort study design, we found that prion infection dramatically lowered survival of free-ranging adult (>2-year-old mule deer (Odocoileus hemionus: estimated average life expectancy was 5.2 additional years for uninfected deer but only 1.6 additional years for infected deer. Prion infection also increased nearly fourfold the rate of mountain lions (Puma concolor preying on deer, suggesting that epidemics may alter predator-prey dynamics by facilitating hunting success. Despite selective predation, about one fourth of the adult deer we sampled were infected. High prevalence and low survival of infected deer provided a plausible explanation for the marked decline in this deer population since the 1980s. CONCLUSION: Remarkably high infection rates sustained in the face of intense predation show that even seemingly complete ecosystems may offer little resistance to the spread and persistence of contagious prion diseases. Moreover, the depression of infected populations may lead to local imbalances in food webs and nutrient cycling in ecosystems in which deer are important herbivores.

  14. Toll-like receptor-mediated immune response inhibits prion propagation.

    Science.gov (United States)

    Kang, Sang-Gyun; Kim, Chiye; Cortez, Leonardo M; Carmen Garza, María; Yang, Jing; Wille, Holger; Sim, Valerie L; Westaway, David; McKenzie, Debbie; Aiken, Judd

    2016-06-01

    Prion diseases are progressive neurodegenerative disorders affecting humans and various mammals. The prominent neuropathological change in prion diseases is neuroinflammation characterized by activation of neuroglia surrounding prion deposition. The cause and effect of this cellular response, however, is unclear. We investigated innate immune defenses against prion infection using primary mixed neuronal and glial cultures. Conditional prion propagation occurred in glial cultures depending on their immune status. Preconditioning of the cells with the toll-like receptor (TLR) ligand, lipopolysaccharide, resulted in a reduction in prion propagation, whereas suppression of the immune responses with the synthetic glucocorticoid, dexamethasone, increased prion propagation. In response to recombinant prion fibrils, glial cells up-regulated TLRs (TLR1 and TLR2) expression and secreted cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6, granulocyte-macrophage colony-stimulating factor, and interferon-β). Preconditioning of neuronal and glial cultures with recombinant prion fibrils inhibited prion replication and altered microglial and astrocytic populations. Our results provide evidence that, in early stages of prion infection, glial cells respond to prion infection through TLR-mediated innate immunity. GLIA 2016;64:937-951. PMID:26880394

  15. The structural stability of wild-type horse prion protein.

    Science.gov (United States)

    Zhang, Jiapu

    2011-10-01

    Prion diseases (e.g. Creutzfeldt-Jakob disease (CJD), variant CJD (vCJD), Gerstmann-Straussler-Scheinker syndrome (GSS), Fatal Familial Insomnia (FFI) and Kuru in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE or 'mad-cow' disease) and chronic wasting disease (CWD) in cattles) are invariably fatal and highly infectious neurodegenerative diseases affecting humans and animals. However, by now there have not been some effective therapeutic approaches or medications to treat all these prion diseases. Rabbits, dogs, and horses are the only mammalian species reported to be resistant to infection from prion diseases isolated from other species. Recently, the β2-α2 loop has been reported to contribute to their protein structural stabilities. The author has found that rabbit prion protein has a strong salt bridge ASP177-ARG163 (like a taut bow string) keeping this loop linked. This paper confirms that this salt bridge also contributes to the structural stability of horse prion protein. Thus, the region of β2-α2 loop might be a potential drug target region. Besides this very important salt bridge, other four important salt bridges GLU196-ARG156-HIS187, ARG156-ASP202 and GLU211-HIS177 are also found to greatly contribute to the structural stability of horse prion protein. Rich databases of salt bridges, hydrogen bonds and hydrophobic contacts for horse prion protein can be found in this paper. PMID:21875155

  16. Thermodynamic Stabilization of the Folded Domain of Prion Protein Inhibits Prion Infection in Vivo

    Directory of Open Access Journals (Sweden)

    Qingzhong Kong

    2013-07-01

    Full Text Available Prion diseases, or transmissible spongiform encephalopathies (TSEs, are associated with the conformational conversion of the cellular prion protein, PrPC, into a protease-resistant form, PrPSc. Here, we show that mutation-induced thermodynamic stabilization of the folded, α-helical domain of PrPC has a dramatic inhibitory effect on the conformational conversion of prion protein in vitro, as well as on the propagation of TSE disease in vivo. Transgenic mice expressing a human prion protein variant with increased thermodynamic stability were found to be much more resistant to infection with the TSE agent than those expressing wild-type human prion protein, in both the primary passage and three subsequent subpassages. These findings not only provide a line of evidence in support of the protein-only model of TSEs but also yield insight into the molecular nature of the PrPC→PrPSc conformational transition, and they suggest an approach to the treatment of prion diseases.

  17. A protein required for prion generation: [URE3] induction requires the Ras-regulated Mks1 protein

    OpenAIRE

    Edskes, Herman K.; Wickner, Reed B.

    2000-01-01

    Infectious proteins (prions) can arise de novo as well as by transmission from another individual. De novo prion generation is believed responsible for most cases of Creutzfeldt–Jakob disease and for initiating the mad cow disease epidemic. However, the cellular components needed for prion generation have not been identified in any system. The [URE3] prion of Saccharomyces cerevisiae is an infectious form of Ure2p, apparently a self-propagating amyloid. We now demonstrate a protein required f...

  18. The sensitive [SWI+] prion: New perspectives on yeast prion diversity

    OpenAIRE

    Hines, Justin K; Craig, Elizabeth A

    2011-01-01

    Yeast prions are heritable protein-based genetic elements which rely on molecular chaperone proteins for stable transmission to cell progeny. Within the past few years, five new prions have been validated and 18 additional putative prions identified in Saccharomyces cerevisiae. The exploration of the physical and biological properties of these “nouveau prions” has begun to reveal the extent of prion diversity in yeast. We recently reported that one such prion, [SWI+], differs from the best st...

  19. Disinfectants and Prions

    Science.gov (United States)

    Prions are novel pathogens that are believed to be composed solely of protein. They are capable of converting a normal cellular protein into the infectious isoform and thereby propagating an infection. Prion infections are characterized by a long asymptomatic incubation period followed by a relative...

  20. Insights into prion protein function from atomistic simulations

    OpenAIRE

    Hodak, Miroslav; Bernholc, Jerzy

    2010-01-01

    Computer simulations are a powerful tool for studies of biological systems. They have often been used to study prion protein (PrP), a protein responsible for neurodegenerative diseases, which include “mad cow disease” in cattle and Creutzfeldt-Jacob disease in humans. An important aspect of the prion protein is its interaction with copper ion, which is thought to be relevant for PrP’s yet undetermined function and also potentially play a role in prion diseases. For studies of copper attachmen...

  1. Synthetic prions and other human neurodegenerative proteinopathies.

    Science.gov (United States)

    Le, Nhat Tran Thanh; Narkiewicz, Joanna; Aulić, Suzana; Salzano, Giulia; Tran, Hoa Thanh; Scaini, Denis; Moda, Fabio; Giachin, Gabriele; Legname, Giuseppe

    2015-09-01

    Transmissible spongiform encephalopathies (TSE) are a heterogeneous group of neurodegenerative disorders. The common feature of these diseases is the pathological conversion of the normal cellular prion protein (PrP(C)) into a β-structure-rich conformer-termed PrP(Sc). The latter can induce a self-perpetuating process leading to amplification and spreading of pathological protein assemblies. Much evidence suggests that PrP(Sc) itself is able to recruit and misfold PrP(C) into the pathological conformation. Recent data have shown that recombinant PrP(C) can be misfolded in vitro and the resulting synthetic conformers are able to induce the conversion of PrP(C) into PrP(Sc)in vivo. In this review we describe the state-of-the-art of the body of literature in this field. In addition, we describe a cell-based assay to test synthetic prions in cells, providing further evidence that synthetic amyloids are able to template conversion of PrP into prion inclusions. Studying prions might help to understand the pathological mechanisms governing other neurodegenerative diseases. Aggregation and deposition of misfolded proteins is a common feature of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other disorders. Although the proteins implicated in each of these diseases differ, they share a common prion mechanism. Recombinant proteins are able to aggregate in vitro into β-rich amyloid fibrils, sharing some features of the aggregates found in the brain. Several studies have reported that intracerebral inoculation of synthetic aggregates lead to unique pathology, which spread progressively to distal brain regions and reduced survival time in animals. Here, we review the prion-like features of different proteins involved in neurodegenerative disorders, such as α-synuclein, superoxide dismutase-1, amyloid-β and tau. PMID:25449570

  2. Synthetic prions and other human neurodegenerative proteinopathies.

    Science.gov (United States)

    Le, Nhat Tran Thanh; Narkiewicz, Joanna; Aulić, Suzana; Salzano, Giulia; Tran, Hoa Thanh; Scaini, Denis; Moda, Fabio; Giachin, Gabriele; Legname, Giuseppe

    2015-09-01

    Transmissible spongiform encephalopathies (TSE) are a heterogeneous group of neurodegenerative disorders. The common feature of these diseases is the pathological conversion of the normal cellular prion protein (PrP(C)) into a β-structure-rich conformer-termed PrP(Sc). The latter can induce a self-perpetuating process leading to amplification and spreading of pathological protein assemblies. Much evidence suggests that PrP(Sc) itself is able to recruit and misfold PrP(C) into the pathological conformation. Recent data have shown that recombinant PrP(C) can be misfolded in vitro and the resulting synthetic conformers are able to induce the conversion of PrP(C) into PrP(Sc)in vivo. In this review we describe the state-of-the-art of the body of literature in this field. In addition, we describe a cell-based assay to test synthetic prions in cells, providing further evidence that synthetic amyloids are able to template conversion of PrP into prion inclusions. Studying prions might help to understand the pathological mechanisms governing other neurodegenerative diseases. Aggregation and deposition of misfolded proteins is a common feature of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other disorders. Although the proteins implicated in each of these diseases differ, they share a common prion mechanism. Recombinant proteins are able to aggregate in vitro into β-rich amyloid fibrils, sharing some features of the aggregates found in the brain. Several studies have reported that intracerebral inoculation of synthetic aggregates lead to unique pathology, which spread progressively to distal brain regions and reduced survival time in animals. Here, we review the prion-like features of different proteins involved in neurodegenerative disorders, such as α-synuclein, superoxide dismutase-1, amyloid-β and tau.

  3. Progress in the development of therapeutic antibodies targeting prion proteins and β-amyloid peptides

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Prion diseases and Alzheimer’s disease (AD) are characterized by protein misfolding, and can lead to dementia. However, prion diseases are infectious and transmissible, while AD is not. The similarities and differences between these diseases have led researchers to perform comparative studies. In the last 2 decades, progress has been made in immunotherapy using anti-prion protein and anti-β-amyloid antibodies. In this study, we review new ideas and strategies for therapeutic antibodies targeting prion diseases and AD through conformation dependence.

  4. Cellular Prion Protein: From Physiology to Pathology

    Directory of Open Access Journals (Sweden)

    Yutaka Kikuchi

    2012-11-01

    Full Text Available The human cellular prion protein (PrPC is a glycosylphosphatidylinositol (GPI anchored membrane glycoprotein with two N-glycosylation sites at residues 181 and 197. This protein migrates in several bands by Western blot analysis (WB. Interestingly, PNGase F treatment of human brain homogenates prior to the WB, which is known to remove the N-glycosylations, unexpectedly gives rise to two dominant bands, which are now known as C-terminal (C1 and N-terminal (N1 fragments. This resembles the β-amyloid precursor protein (APP in Alzheimer disease (AD, which can be physiologically processed by α-, β-, and γ-secretases. The processing of APP has been extensively studied, while the identity of the cellular proteases involved in the proteolysis of PrPC and their possible role in prion biology has remained limited and controversial. Nevertheless, there is a strong correlation between the neurotoxicity caused by prion proteins and the blockade of their normal proteolysis. For example, expression of non-cleavable PrPC mutants in transgenic mice generates neurotoxicity, even in the absence of infectious prions, suggesting that PrPC proteolysis is physiologically and pathologically important. As many mouse models of prion diseases have recently been developed and the knowledge about the proteases responsible for the PrPC proteolysis is accumulating, we examine the historical experimental evidence and highlight recent studies that shed new light on this issue.

  5. A Micellar On-Pathway Intermediate Step Explains the Kinetics of Prion Amyloid Formation

    OpenAIRE

    Erwan Hingant; Pascaline Fontes; Maria Teresa Alvarez-Martinez; Jacques-Damien Arnaud; Jean-Pierre Liautard; Laurent Pujo-Menjouet

    2014-01-01

    Author Summary Understanding the mechanism of prions is an important issue. Indeed, it involves a mechanism modifying the structure of the proteins that are of high interest in theoretical biology. Knowing the underlying mechanism that leads to prion disease could help further investigations in the world of amyloid disease and for example the so-called Alzheimer's disease. The theory of prion, also known as Protein-Only, has been widely studied. Nevertheless no mathematical models are able to...

  6. Prion疾病与生物无机化学%Prion Diseases and Bio-inorganic Chemistry

    Institute of Scientific and Technical Information of China (English)

    黄仲贤; 陆君霞; 王韵华

    2000-01-01

    介绍了除病菌、病毒以外的第三种病原体-病蛋白Prion.这种病原蛋白的本质是正常蛋白的异常折叠,因此又被称为蛋白分子的"构象病".还介绍了这种病蛋白的可能致病机理.铜离子对这种病蛋白生成的重要作用,充分显示了生物无机化学这门新兴学科的重要性和前沿性.

  7. Normal modes of prion proteins: from native to infectious particle.

    Science.gov (United States)

    Samson, Abraham O; Levitt, Michael

    2011-03-29

    Prion proteins (PrP) are the infectious agent in transmissible spongiform encephalopathies (i.e., mad cow disease). To be infectious, prion proteins must undergo a conformational change involving a decrease in α-helical content along with an increase in β-strand content. This conformational change was evaluated by means of elastic normal modes. Elastic normal modes show a diminution of two α-helices by one and two residues, as well as an extension of two β-strands by three residues each, which could instigate the conformational change. The conformational change occurs in a region that is compatible with immunological studies, and it is observed more frequently in mutant prions that are prone to conversion than in wild-type prions because of differences in their starting structures, which are amplified through normal modes. These findings are valuable for our comprehension of the conversion mechanism associated with the conformational change in prion proteins. PMID:21338080

  8. Resistance of soil-bound prions to rumen digestion.

    Directory of Open Access Journals (Sweden)

    Samuel E Saunders

    Full Text Available Before prion uptake and infection can occur in the lower gastrointestinal system, ingested prions are subjected to anaerobic digestion in the rumen of cervids and bovids. The susceptibility of soil-bound prions to rumen digestion has not been evaluated previously. In this study, prions from infectious brain homogenates as well as prions bound to a range of soils and soil minerals were subjected to in vitro rumen digestion, and changes in PrP levels were measured via western blot. Binding to clay appeared to protect noninfectious hamster PrP(c from complete digestion, while both unbound and soil-bound infectious PrP(Sc proved highly resistant to rumen digestion. In addition, no change in intracerebral incubation period was observed following active rumen digestion of unbound hamster HY TME prions and HY TME prions bound to a silty clay loam soil. These results demonstrate that both unbound and soil-bound prions readily survive rumen digestion without a reduction in infectivity, further supporting the potential for soil-mediated transmission of chronic wasting disease (CWD and scrapie in the environment.

  9. Prion protein in milk.

    Directory of Open Access Journals (Sweden)

    Nicola Franscini

    Full Text Available BACKGROUND: Prions are known to cause transmissible spongiform encephalopathies (TSE after accumulation in the central nervous system. There is increasing evidence that prions are also present in body fluids and that prion infection by blood transmission is possible. The low concentration of the proteinaceous agent in body fluids and its long incubation time complicate epidemiologic analysis and estimation of spreading and thus the risk of human infection. This situation is particularly unsatisfactory for food and pharmaceutical industries, given the lack of sensitive tools for monitoring the infectious agent. METHODOLOGY/PRINCIPAL FINDINGS: We have developed an adsorption matrix, Alicon PrioTrap, which binds with high affinity and specificity to prion proteins. Thus we were able to identify prion protein (PrP(C--the precursor of prions (PrP(Sc--in milk from humans, cows, sheep, and goats. The absolute amount of PrP(C differs between the species (from microg/l range in sheep to ng/l range in human milk. PrP(C is also found in homogenised and pasteurised off-the-shelf milk, and even ultrahigh temperature treatment only partially diminishes endogenous PrP(C concentration. CONCLUSIONS/SIGNIFICANCE: In view of a recent study showing evidence of prion replication occurring in the mammary gland of scrapie infected sheep suffering from mastitis, the appearance of PrP(C in milk implies the possibility that milk of TSE-infected animals serves as source for PrP(Sc.

  10. Molecular dynamics studies on the structural stability of wild-type dog prion protein.

    Science.gov (United States)

    Zhang, Jiapu; Liu, David D W

    2011-06-01

    Prion diseases such as Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob diseases, Gerstmann-Sträussler-Scheinker syndrome, Fatal Familial Insomnia, Kuru in humans, scrapie in sheep, bovine spongiform encephalopathy (or 'mad-cow' disease) and chronic wasting disease in cattle are invariably fatal and highly infectious neurodegenerative diseases affecting humans and animals. However, by now there have not been some effective therapeutic approaches to treat all these prion diseases. In 2008, canine mammals including dogs (canis familials) were the first time academically reported to be resistant to prion diseases (Vaccine 26: 2601-2614 (2008)). Thus, it is very worth studying the molecular structures of dog prion protein to obtain insights into the immunity of dogs to prion diseases. This paper studies the molecular structural dynamics of wild-type dog prion protein. The comparison analyses with rabbit prion protein show that the dog prion protein has stable molecular structures whether under neutral or low pH environments. We also find that the salt bridges such as D177-R163 contribute to the structural stability of wild-type rabbit prion protein under neutral pH environment. PMID:21469747

  11. Bank Vole Prion Protein As an Apparently Universal Substrate for RT-QuIC-Based Detection and Discrimination of Prion Strains.

    Science.gov (United States)

    Orrú, Christina D; Groveman, Bradley R; Raymond, Lynne D; Hughson, Andrew G; Nonno, Romolo; Zou, Wenquan; Ghetti, Bernardino; Gambetti, Pierluigi; Caughey, Byron

    2015-06-01

    Prions propagate as multiple strains in a wide variety of mammalian species. The detection of all such strains by a single ultrasensitive assay such as Real Time Quaking-induced Conversion (RT-QuIC) would facilitate prion disease diagnosis, surveillance and research. Previous studies have shown that bank voles, and transgenic mice expressing bank vole prion protein, are susceptible to most, if not all, types of prions. Here we show that bacterially expressed recombinant bank vole prion protein (residues 23-230) is an effective substrate for the sensitive RT-QuIC detection of all of the different prion types that we have tested so far--a total of 28 from humans, cattle, sheep, cervids and rodents, including several that have previously been undetectable by RT-QuIC or Protein Misfolding Cyclic Amplification. Furthermore, comparison of the relative abilities of different prions to seed positive RT-QuIC reactions with bank vole and not other recombinant prion proteins allowed discrimination of prion strains such as classical and atypical L-type bovine spongiform encephalopathy, classical and atypical Nor98 scrapie in sheep, and sporadic and variant Creutzfeldt-Jakob disease in humans. Comparison of protease-resistant RT-QuIC conversion products also aided strain discrimination and suggested the existence of several distinct classes of prion templates among the many strains tested.

  12. Prion protein and susceptibility to kainate-induced seizures

    OpenAIRE

    Striebel, James F.; Race, Brent; Chesebro, Bruce

    2013-01-01

    Prion protein (PrP) is a cell surface glycoprotein which is required for susceptibility to prion infection and disease. However, PrP is expressed in many different cell types located in numerous organs. Therefore, in addition to its role in prion diseases, PrP may have a large variety of other biological functions involving the nervous system and other systems. We recently showed that susceptibility to kainate-induced seizures differed in Prnp−/− and Prnp+/+ mice on the C57BL/10SnJ background...

  13. Rapid antemortem detection of CWD prions in deer saliva.

    Directory of Open Access Journals (Sweden)

    Davin M Henderson

    Full Text Available Chronic wasting disease (CWD is an efficiently transmitted prion disease of cervids, now identified in 22 United States, 2 Canadian provinces and Korea. One hallmark of CWD is the shedding of infectious prions in saliva, as demonstrated by bioassay in deer. It is also clear that the concentration of prions in saliva, blood, urine and feces is much lower than in the nervous system or lymphoid tissues. Rapid in vitro detection of CWD (and other prions in body fluids and excreta has been problematic due to the sensitivity limits of direct assays (western blotting, ELISA and the presence of inhibitors in these complex biological materials that hamper detection. Here we use real-time quaking induced conversion (RT-QuIC to demonstrate CWD prions in both diluted and prion-enriched saliva samples from asymptomatic and symptomatic white-tailed deer. CWD prions were detected in 14 of 24 (58.3% diluted saliva samples from CWD-exposed white-tailed deer, including 9 of 14 asymptomatic animals (64.2%. In addition, a phosphotungstic acid enrichment enhanced the RT-QuIC assay sensitivity, enabling detection in 19 of 24 (79.1% of the above saliva samples. Bioassay in Tg[CerPrP] mice confirmed the presence of infectious prions in 2 of 2 RT-QuIC-positive saliva samples so examined. The modified RT-QuIC analysis described represents a non-invasive, rapid ante-mortem detection of prions in complex biologic fluids, excreta, or environmental samples as well as a tool for exploring prion trafficking, peripheralization, and dissemination.

  14. Stimulating the Release of Exosomes Increases the Intercellular Transfer of Prions.

    Science.gov (United States)

    Guo, Belinda B; Bellingham, Shayne A; Hill, Andrew F

    2016-03-01

    Exosomes are small extracellular vesicles released by cells and play important roles in intercellular communication and pathogen transfer. Exosomes have been implicated in several neurodegenerative diseases, including prion disease and Alzheimer disease. Prion disease arises upon misfolding of the normal cellular prion protein, PrP(C), into the disease-associated isoform, PrP(Sc). The disease has a unique transmissible etiology, and exosomes represent a novel and efficient method for prion transmission. The precise mechanism by which prions are transmitted from cell to cell remains to be fully elucidated, although three hypotheses have been proposed: direct cell-cell contact, tunneling nanotubes, and exosomes. Given the reported presence of exosomes in biological fluids and in the lipid and nucleic acid contents of exosomes, these vesicles represent an ideal mechanism for encapsulating prions and potential cofactors to facilitate prion transmission. This study investigates the relationship between exosome release and intercellular prion dissemination. Stimulation of exosome release through treatment with an ionophore, monensin, revealed a corresponding increase in intercellular transfer of prion infectivity. Conversely, inhibition of exosome release using GW4869 to target the neutral sphingomyelinase pathway induced a decrease in intercellular prion transmission. Further examination of the effect of monensin on PrP conversion revealed that monensin also alters the conformational stability of PrP(C), leading to increased generation of proteinase K-resistant prion protein. The findings presented here provide support for a positive relationship between exosome release and intercellular transfer of prion infectivity, highlighting an integral role for exosomes in facilitating the unique transmissible nature of prions.

  15. Stimulating the Release of Exosomes Increases the Intercellular Transfer of Prions.

    Science.gov (United States)

    Guo, Belinda B; Bellingham, Shayne A; Hill, Andrew F

    2016-03-01

    Exosomes are small extracellular vesicles released by cells and play important roles in intercellular communication and pathogen transfer. Exosomes have been implicated in several neurodegenerative diseases, including prion disease and Alzheimer disease. Prion disease arises upon misfolding of the normal cellular prion protein, PrP(C), into the disease-associated isoform, PrP(Sc). The disease has a unique transmissible etiology, and exosomes represent a novel and efficient method for prion transmission. The precise mechanism by which prions are transmitted from cell to cell remains to be fully elucidated, although three hypotheses have been proposed: direct cell-cell contact, tunneling nanotubes, and exosomes. Given the reported presence of exosomes in biological fluids and in the lipid and nucleic acid contents of exosomes, these vesicles represent an ideal mechanism for encapsulating prions and potential cofactors to facilitate prion transmission. This study investigates the relationship between exosome release and intercellular prion dissemination. Stimulation of exosome release through treatment with an ionophore, monensin, revealed a corresponding increase in intercellular transfer of prion infectivity. Conversely, inhibition of exosome release using GW4869 to target the neutral sphingomyelinase pathway induced a decrease in intercellular prion transmission. Further examination of the effect of monensin on PrP conversion revealed that monensin also alters the conformational stability of PrP(C), leading to increased generation of proteinase K-resistant prion protein. The findings presented here provide support for a positive relationship between exosome release and intercellular transfer of prion infectivity, highlighting an integral role for exosomes in facilitating the unique transmissible nature of prions. PMID:26769968

  16. Discovery of a novel, monocationic, small-molecule inhibitor of scrapie prion accumulation in cultured sheep microglia and rov cells PLoS one

    Science.gov (United States)

    Prion diseases, including sheep scrapie are neurodegenerative diseases with the fundamental pathogenesis involving conversion of normal cellular prion protein (PrPC) to disease-associated prion protein (PrPSc). An aromatic monocationic furamidine analogue (DB772), which has previously demonstrated a...

  17. Role of Prion Protein Aggregation in Neurotoxicity

    Directory of Open Access Journals (Sweden)

    Tullio Florio

    2012-07-01

    Full Text Available In several neurodegenerative diseases, such as Parkinson, Alzheimer’s, Huntington, and prion diseases, the deposition of aggregated misfolded proteins is believed to be responsible for the neurotoxicity that characterizes these diseases. Prion protein (PrP, the protein responsible of prion diseases, has been deeply studied for the peculiar feature of its misfolded oligomers that are able to propagate within affected brains, inducing the conversion of the natively folded PrP into the pathological conformation. In this review, we summarize the available experimental evidence concerning the relationship between aggregation status of misfolded PrP and neuronal death in the course of prion diseases. In particular, we describe the main findings resulting from the use of different synthetic (mainly PrP106-126 and recombinant PrP-derived peptides, as far as mechanisms of aggregation and amyloid formation, and how these different spatial conformations can affect neuronal death. In particular, most data support the involvement of non-fibrillar oligomers rather than actual amyloid fibers as the determinant of neuronal death.

  18. Inactivation of prion infectivity by ionizing rays

    International Nuclear Information System (INIS)

    Inactivation of prion deposits on medical devices or prion contamination in pharmaceutical raw materials is considered as impossible by using gamma irradiation. Early, the guideline WHO/CDS/CSR/APH/2000 has described irradiation as an ineffective process. But, in 2003, S. Miekka et al. noted radiation inactivation of prions in a particular application to purify human albumin, shown by the physical denaturation of the infectious protein (PrP). The aim of our study was to determine the inactivation of prions with a scrapie model (strain C506M3) by irradiating standardised preparations. Results: Gamma irradiation was partially effective, showing a 4-5 log reduction on exposure to 50 kGy. A characteristic effect-dose curve was not observed (25, 50 and 100 kGy), only an increase in the incubation period of the murine disease (229 days with 25 kGy to 290 days with 100 kGy) compared with 170 days without irradiation. Since the inactivation was not a total one, the observed effect is significant. It is proposed that further work be undertaken with the model to investigate the application of gamma radiation known levels of prion contamination

  19. Inactivation of prion infectivity by ionizing rays

    Energy Technology Data Exchange (ETDEWEB)

    Gominet, M. [Ionisos, ZI les Chatinieres, F01120 Dagneux (France); Vadrot, C.; Austruy, G. [Paris V University, Central Pharmacy of Hospitals, 4 avenue de l' Observatoire, F-75006, Paris (France); Darbord, J.C. [Paris V University, Central Pharmacy of Hospitals, 4 avenue de l' Observatoire, F-75006, Paris (France)], E-mail: darbord@pharmacie.univ-paris5.fr

    2007-11-15

    Inactivation of prion deposits on medical devices or prion contamination in pharmaceutical raw materials is considered as impossible by using gamma irradiation. Early, the guideline WHO/CDS/CSR/APH/2000 has described irradiation as an ineffective process. But, in 2003, S. Miekka et al. noted radiation inactivation of prions in a particular application to purify human albumin, shown by the physical denaturation of the infectious protein (PrP). The aim of our study was to determine the inactivation of prions with a scrapie model (strain C506M3) by irradiating standardised preparations. Results: Gamma irradiation was partially effective, showing a 4-5 log reduction on exposure to 50 kGy. A characteristic effect-dose curve was not observed (25, 50 and 100 kGy), only an increase in the incubation period of the murine disease (229 days with 25 kGy to 290 days with 100 kGy) compared with 170 days without irradiation. Since the inactivation was not a total one, the observed effect is significant. It is proposed that further work be undertaken with the model to investigate the application of gamma radiation known levels of prion contamination.

  20. Inactivation of prion infectivity by ionizing rays

    Science.gov (United States)

    Gominet, M.; Vadrot, C.; Austruy, G.; Darbord, J. C.

    2007-11-01

    Inactivation of prion deposits on medical devices or prion contamination in pharmaceutical raw materials is considered as impossible by using gamma irradiation. Early, the guideline WHO/CDS/CSR/APH/2000 has described irradiation as an ineffective process. But, in 2003, S. Miekka et al. noted radiation inactivation of prions in a particular application to purify human albumin, shown by the physical denaturation of the infectious protein (PrP). The aim of our study was to determine the inactivation of prions with a scrapie model (strain C506M3) by irradiating standardised preparations. Results: Gamma irradiation was partially effective, showing a 4-5 log reduction on exposure to 50 kGy. A characteristic effect-dose curve was not observed (25, 50 and 100 kGy), only an increase in the incubation period of the murine disease (229 days with 25 kGy to 290 days with 100 kGy) compared with 170 days without irradiation. Since the inactivation was not a total one, the observed effect is significant. It is proposed that further work be undertaken with the model to investigate the application of gamma radiation known levels of prion contamination.

  1. Truncated forms of the prion protein PrP demonstrate the need for complexity in prion structure.

    Science.gov (United States)

    Wan, William; Stöhr, Jan; Kendall, Amy; Stubbs, Gerald

    2015-01-01

    Self-propagation of aberrant protein folds is the defining characteristic of prions. Knowing the structural basis of self-propagation is essential to understanding prions and their related diseases. Prion rods are amyloid fibrils, but not all amyloids are prions. Prions have been remarkably intractable to structural studies, so many investigators have preferred to work with peptide fragments, particularly in the case of the mammalian prion protein PrP. We compared the structures of a number of fragments of PrP by X-ray fiber diffraction, and found that although all of the peptides adopted amyloid conformations, only the larger fragments adopted conformations that modeled the complexity of self-propagating prions, and even these fragments did not always adopt the PrP structure. It appears that the relatively complex structure of the prion form of PrP is not accessible to short model peptides, and that self-propagation may be tied to a level of structural complexity unobtainable in simple model systems. The larger fragments of PrP, however, are useful to illustrate the phenomenon of deformed templating (heterogeneous seeding), which has important biological consequences.

  2. Clinical studies on thyroid diseases

    OpenAIRE

    Fliers, E.; Wiersinga, W.M.; Eskes, S.A.

    2014-01-01

    This thesis focuses on some aspects of thyroid disease: prevention of autoimmune thyroid disease (AITD), diagnosis of related conditions as autoimmune hypophysitis in autoimmune hypothyroidism (Hashimoto’s disease), and treatment of amiodarone-induced thyrotoxicosis (AIT).

  3. A survey and a molecular dynamics study on the (central) hydrophobic region of prion proteins.

    Science.gov (United States)

    Zhang, Jiapu; Wang, Feng

    2014-01-01

    Prion diseases which are serious neurodegenerative diseases that affect humans and animals occur in various of species. Unlike many other neurodegenerative diseases affected by amyloid, prion diseases can be highly infectious. Prion diseases occur in many species. In humans, prion diseases include the fatal human neurodegenerative diseases such as Creutzfeldt-Jakob Disease (CJD), Fatal Familial Insomnia (FFI), Gerstmann-Strussler-Scheinker syndrome (GSS) and Kuru etc. In animals, prion diseases are related to the bovine spongiform encephalopathy (BSE or 'mad-cow' disease) in cattle, the chronic wasting disease (CWD) found in deer and elk, and scrapie seen in sheep and goats, etc. More seriously, the fact that transmission of the prion diseases across the species barrier to other species such as humans has caused a major public health concern worldwide. For example, the BSE in Europe, the CWD in North America, and variant CJDs (vCJDs) in young people of UK. Fortunately, it is discovered that the hydrophobic region of prion proteins (PrP) controls the formation of diseased prions (PrP(Sc)), which provide some clues in control of such diseases. This article provides a detailed survey of recent studies with respect to the PrP hydrophobic region of human PrP(110-136) using molecular dynamics studies. PMID:25373387

  4. The saga of prion: to cut or not to cut

    Institute of Scientific and Technical Information of China (English)

    Man-Sun Sy

    2009-01-01

    @@ Transmissible Spongiform Enceph-aiopathies (TSE), commonly referred to as prion diseases, are a group of rare, infectious and fatal neurodegenerative diseases in mammals [1]. All prion diseases are thought to share a common pathogenic mechanism, which is based on the conversion of the normal cellu-lar prion, PrPC, into the infectious and pathogenic scrapie prion protein, PrPSc [2, 3]. The accumulation ofPrPSc in the CNS is then thought to impair function, induce structural damage, and cause disease. In addition to gain of toxic function, loss of normal PrPC function, a consequence of conversion to PrPSc may also contribute to pathogenesis [4].

  5. Role of lipid in forming an infectious prion?

    Institute of Scientific and Technical Information of China (English)

    Fei Wang; Jiyan Ma

    2013-01-01

    The infectious agent of the transmissible spongiform encephalopathies,or prion diseases,has been the center of intense debate for decades.Years of studies have provided overwhelming evidence to support the prion hypothesis that posits a protein conformal infectious agent is responsible for the transmissibility of the disease.The recent studies that generate prion infectivity with purified bacterially expressed recombinant prion protein not only provides convincing evidence supporting the core of the prion hypothesis,that a pathogenic conformer of host prion protein is able to seed the conversion of its normal counterpart to the likeness of itself resulting in the replication of the pathogenic conformer and occurrence of disease,they also indicate the importance of cofactors,particularly lipid or lipid-like molecules,in forming the protein conformation-based infectious agent.This article reviews the literature regarding the chemical nature of the infectious agent and the potential contribution from lipid molecules to prion infectivity,and discusses the important remaining questions in this research area.

  6. MDS clinical diagnostic criteria for Parkinson's disease

    NARCIS (Netherlands)

    Postuma, R.B.; Berg, D; Stern, M.; Poewe, W.; Olanow, C.W.; Oertel, W.; Obeso, J.; Marek, K.; Litvan, I.; Lang, A.E.; Halliday, G.; Goetz, C.G.; Gasser, T.; Dubois, B.; Chan, P.; Bloem, B.R.; Adler, C.H.; Deuschl, G.

    2015-01-01

    This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical di

  7. Infectious Disease Clinical Research Program (IDCRP)

    Data.gov (United States)

    Federal Laboratory Consortium — Our mission is to conduct infectious disease clinical research of importance to the military through a unique, adaptive, and collaborative network, to inform health...

  8. Persistence of pathogenic prion protein during simulated wastewater treatment processes

    Science.gov (United States)

    Hinckley, G.T.; Johnson, C.J.; Jacobson, K.H.; Bartholomay, C.; Mcmahon, K.D.; McKenzie, D.; Aiken, Judd M.; Pedersen, J.A.

    2008-01-01

    Transmissible spongiform encephalopathies (TSEs, prion diseases) are a class of fatal neurodegenerative diseases affecting a variety of mammalian species including humans. A misfolded form of the prion protein (PrP TSE) is the major, if not sole, component of the infectious agent. Prions are highly resistant to degradation and to many disinfection procedures suggesting that, if prions enter wastewater treatment systems through sewers and/or septic systems (e.g., from slaughterhouses, necropsy laboratories, rural meat processors, private game dressing) or through leachate from landfills that have received TSE-contaminated material, prions could survive conventional wastewater treatment Here, we report the results of experiments examining the partitioning and persistence of PrPTSE during simulated wastewater treatment processes including activated and mesophilic anaerobic sludge digestion. Incubation with activated sludge did not result in significant PrPTSE degradation. PrPTSE and prion infectivity partitioned strongly to activated sludge solids and are expected to enter biosolids treatment processes. A large fraction of PrPTSE survived simulated mesophilic anaerobic sludge digestion. The small reduction in recoverable PrPTSE after 20-d anaerobic sludge digestion appeared attributable to a combination of declining extractability with time and microbial degradation. Our results suggest that if prions were to enter municipal wastewater treatment systems, most would partition to activated sludge solids, survive mesophilic anaerobic digestion, and be present in treated biosolids. ?? 2008 American Chemical Society.

  9. Protease-resistant prions selectively decrease Shadoo protein.

    Directory of Open Access Journals (Sweden)

    Joel C Watts

    2011-11-01

    Full Text Available The central event in prion diseases is the conformational conversion of the cellular prion protein (PrP(C into PrP(Sc, a partially protease-resistant and infectious conformer. However, the mechanism by which PrP(Sc causes neuronal dysfunction remains poorly understood. Levels of Shadoo (Sho, a protein that resembles the flexibly disordered N-terminal domain of PrP(C, were found to be reduced in the brains of mice infected with the RML strain of prions [1], implying that Sho levels may reflect the presence of PrP(Sc in the brain. To test this hypothesis, we examined levels of Sho during prion infection using a variety of experimental systems. Sho protein levels were decreased in the brains of mice, hamsters, voles, and sheep infected with different natural and experimental prion strains. Furthermore, Sho levels were decreased in the brains of prion-infected, transgenic mice overexpressing Sho and in infected neuroblastoma cells. Time-course experiments revealed that Sho levels were inversely proportional to levels of protease-resistant PrP(Sc. Membrane anchoring and the N-terminal domain of PrP both influenced the inverse relationship between Sho and PrP(Sc. Although increased Sho levels had no discernible effect on prion replication in mice, we conclude that Sho is the first non-PrP marker specific for prion disease. Additional studies using this paradigm may provide insight into the cellular pathways and systems subverted by PrP(Sc during prion disease.

  10. Preclinical deposition of pathological prion protein in muscle of experimentally infected primates.

    Directory of Open Access Journals (Sweden)

    Susanne Krasemann

    Full Text Available Prion diseases are transmissible fatal neurodegenerative disorders affecting humans and animals. A central step in disease progression is the accumulation of a misfolded form (PrP(Sc of the host encoded prion protein (PrP(C in neuronal and non-neuronal tissues. The involvement of peripheral tissues in preclinical states increases the risk of accidental transmission. On the other hand, detection of PrP(Sc in non-neuronal easy-accessible compartments such as muscle may offer a novel diagnostic tool. Primate models have proven invaluable to investigate prion diseases. We have studied the deposition of PrP(Sc in muscle and central nervous system of rhesus monkeys challenged with sporadic Creutzfeldt-Jakob disease (sCJD, variant CJD (vCJD and bovine spongiform encephalopathy (BSE in preclinical and clinical stage using biochemical and morphological methods. Here, we show the preclinical presence of PrP(Sc in muscle and central nervous system of rhesus monkeys experimentally infected with vCJD.

  11. Inactivation of Prions by Acidic Sodium Dodecyl Sulfate

    OpenAIRE

    Peretz, David; Supattapone, Surachai; Giles, Kurt; Vergara, Julie; Freyman, Yevgeniy; Lessard, Pierre; Safar, Jiri G; Glidden, David V.; McCulloch, Charles; Nguyen, Hoang-Oanh B.; Scott, Michael; Stephen J DeArmond; Prusiner, Stanley B.

    2006-01-01

    Prompted by the discovery that prions become protease-sensitive after exposure to branched polyamine dendrimers in acetic acid (AcOH) (S. Supattapone, H. Wille, L. Uyechi, J. Safar, P. Tremblay, F. C. Szoka, F. E. Cohen, S. B. Prusiner, and M. R. Scott, J. Virol. 75:3453-3461, 2001), we investigated the inactivation of prions by sodium dodecyl sulfate (SDS) in weak acid. As judged by sensitivity to proteolytic digestion, the disease-causing prion protein (PrPSc) was denatured at room temperat...

  12. Insights into prion protein function from atomistic simulations.

    Science.gov (United States)

    Hodak, Miroslav; Bernholc, Jerzy

    2010-01-01

    Computer simulations are a powerful tool for studies of biological systems. They have often been used to study prion protein (PrP), a protein responsible for neurodegenerative diseases, which include "mad cow disease" in cattle and Creutzfeldt-Jacob disease in humans. An important aspect of the prion protein is its interaction with copper ion, which is thought to be relevant for PrP's yet undetermined function and also potentially play a role in prion diseases. for studies of copper attachment to the prion protein, computer simulations have often been used to complement experimental data and to obtain binding structures of Cu-PrP complexes. This paper summarizes the results of recent ab initio calculations of copper-prion protein interactions focusing on the recently discovered concentration-dependent binding modes in the octarepeat region of this protein. In addition to determining the binding structures, computer simulations were also used to make predictions about PrP's function and the role of copper in prion diseases. The results demonstrate the predictive power and applicability of ab initio simulations for studies of metal-biomolecular complexes. PMID:20118658

  13. Influence of prion strain on prion protein adsorption to soil in a competitive matrix.

    Science.gov (United States)

    Saunders, Samuel E; Bartz, Jason C; Bartelt-Hunt, Shannon L

    2009-07-15

    It is likely that the soil environment serves as a stable reservoir of infectious chronic wasting disease (CWD) and scrapie prions, as well as a potential reservoir of bovine spongiform encephalopathy (BSE, or "mad cow" disease). Prion adsorption to soil may play an important role in prion mobility, proteolysis, and infectivity. Differences in PrP environmental fate are possible due to the strain- and species-dependent structure of PrP(Sc). Kinetic and isothermal studies of PrP adsorption to sand and two whole soils were conducted using HY and DY TME-infected hamster, uninfected hamster, and CWD-infected elk brain homogenates as competitive PrP sources. The role of the N-terminus in PrP adsorption was also investigated. We report strain and species differences in PrP adsorption to soil over time and as a function of aqueous concentration, indicating that the fate of prions in the environment may vary with the prion strain and species infected. Our data also provide evidence that the N-terminal region of PrP enhances adsorption to clay but may hinder adsorption to sand. PrP adsorption was maximal at an intermediate aqueous concentration, most likely due to the competitive brain homogenate matrix in which it enters the soil environment. PMID:19708348

  14. Detecting and discriminating among pathogenic protein conformers(prions), using mass spectrometry-based and antibody-based approaches(Abstract)

    Science.gov (United States)

    A set of fatal neurological diseases that includes scrapie and chronic wasting disease (CWD) are caused by a pathological protein referred to as a prion (PrPSc). A prion propagates an infection by converting a normal cellular protein (PrPC) into a prion. Unlike viral, bacterial, or fungal pathogens,...

  15. THERAPIES FOR CROHN'S DISEASE: a clinical update.

    Science.gov (United States)

    Sobrado, Carlos Walter; Leal, Raquel Franco; Sobrado, Lucas Faraco

    2016-01-01

    The main objectives of clinical therapy in Crohn's disease are clinical and endoscopic remission without the use of corticosteroids for long periods of time, prevention of hospitalization and surgery, and improvement of quality of life. The main limitation of drug therapy is the loss of response over the long term, which makes incorporation of new drugs to the therapeutic arsenal necessary. This review analyses the main drugs currently used in clinical treatment of Crohn's disease. PMID:27438429

  16. Alzheimer's Disease Brain-Derived Amyloid-{beta}-Mediated Inhibition of LTP In Vivo Is Prevented by Immunotargeting Cellular Prion Protein.

    LENUS (Irish Health Repository)

    Barry, Andrew E

    2011-05-18

    Synthetic amyloid-β protein (Aβ) oligomers bind with high affinity to cellular prion protein (PrP(C)), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aβ in vitro is controversial. Here we report that intracerebroventricular injection of Aβ-containing aqueous extracts of Alzheimer\\'s disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aβ. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aβ-binding site on PrP(C), prevented the inhibition of LTP by AD brain-derived Aβ. In contrast, R1, a Fab directed to the C terminus of PrP(C), a region not implicated in binding of Aβ, did not significantly affect the Aβ-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aβ dimer and the role of PrP(C) in mediating synaptic plasticity disruption by soluble Aβ.

  17. Prion protein gene heterogeneity in free-ranging white-tailed deer within the chronic wasting disease affected region of Wisconsin.

    Science.gov (United States)

    Johnson, Chad; Johnson, Jody; Clayton, Murray; McKenzie, Debbie; Aiken, Judd

    2003-07-01

    Chronic wasting disease (CWD) was first identified in Wisconsin (USA) in whitetailed deer (Odocoileus virginianus) in February 2002. To determine if prion protein gene (Prnp) allelic variability was associated with CWD in white-tailed deer from Wisconsin, we sequenced Prnp from 26 CWD-positive and 100 CWD-negative deer. Sequence analysis of Prnp suggests that at least 86-96% of the white-tailed deer in this region have Prnp allelic combinations that will support CWD infection. Four Prnp alleles were identified in the deer population, one of which, resulting in a glutamine to histidine change at codon 95, has not been previously reported. The predominant allele in the population encodes for glutamine at codon 95, glycine at codon 96, and serine at codon 138 (QGS). Less abundant alleles encoded QSS, QGN, and HGS at the three variable positions. Comparison of CWD-positive with CWD-negative deer suggested a trend towards an over-representation of the QGS allele and an under-representation of the QSS allele.

  18. Polymorphisms at codons 56 and 174 of the prion-like protein gene (PRND) are not associated with sporadic Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Jeong, Byung-Hoon; Kim, Nam-Ho; Kim, Jae-Il; Carp, Richard I; Kim, Yong-Sun

    2005-01-01

    Association between sporadic Creutzfeldt-Jakob disease (CJD) and the prion-like protein gene (PRND) has been reported in the German population. To investigate whether the PRND polymorphisms are associated with an increased risk for developing sporadic CJD in the Korean population, we compared the genotype and allele frequencies of PRND polymorphisms in 110 sporadic CJD patients with those in 102 healthy Koreans. Two polymorphisms (P56L, T174 M) in Koreans were found in the open reading frame (ORF) of PRND. One heterozygote of P56L was observed in normal controls but not in sporadic CJD patients. A strong significant difference of PRND genotype frequency at codon 174 was found between the normal Korean population and various European populations. In contrast to results in the German population, our study did not show a significant difference in PRND genotype or allele frequency at codon 174 between sporadic CJD and normal controls. This was the first genetic association study of the ORF of PRND in an Asian CJD population.

  19. Monitoring prion protein stability by NMR.

    Science.gov (United States)

    Julien, Olivier; Graether, Steffen P; Sykes, Brian D

    2009-01-01

    Prion diseases, or transmissible spongiform encephalopathies (TSE), are a group of fatal neurological diseases that affect both humans and animals. At the end of the 20th century, bovine spongiform encephalopathy (BSE), better known as mad cow disease, was shown to be transmissible to humans. This resulted in considerable concern for public health and a number of questions for scientists. The first question answered was the possible source of the disease, which appears to be the prion protein (PrP). There are two major forms of this protein: the native, noninfectious form (PrP(C)), and the misfolded infectious form (PrP(Sc)). PrP(C) is mainly alpha-helical in structure, whereas PrP(Sc) aggregates into an assembly of beta-sheets, forming amyloid fibrils. Since the first solution structure of the noninfectious form of the mouse prion protein, about 30 structures of the globular portion of PrP(C) have been characterized from different organisms. However, only a few minor differences are observed when comparing one PrP(C) structure to another. The key to understanding prion formation may then be not in the structure of PrP(C), but in the mechanism underlying PrP(C) unfolding and then conversion into a misfolded fibril state. To identify the possible region(s) of PrP(C) responsible for initiating the conversion into the amyloid fibril formation, nuclear magnetic resonance (NMR) was applied to characterize the stability and structure of PrP(C) and intermediate states during the conversion from PrP(C) to PrP(Sc). Subsequently urea was used to induce unfolding, and data analysis revealed region-specific structural stabilities that may bring insights into the mechanisms underlying conversion of protein into an infectious prion. PMID:19697241

  20. Atomic-resolution structures of prion AGAAAAGA amyloid fibrils

    CERN Document Server

    Zhang, Jiapu

    2011-01-01

    To the best of the author's knowledge, there is little structural data available on the AGAAAAGA palindrome in the hydrophobic region (113-120) of prion proteins due to the unstable, noncrystalline and insoluble nature of the amyloid fibril, although many experimental studies have shown that this region has amyloid fibril forming properties and plays an important role in prion diseases. In view of this, the present study is devoted to address this problem from computational approaches such as local optimization steepest descent, conjugate gradient, discrete gradient and Newton methods, global optimization simulated annealing and genetic algorithms, canonical dual optimization theory, and structural bioinformatics. The optimal atomic-resolution structures of prion AGAAAAGA amyloid fibils reported in this Chapter have a value to the scientific community in its drive to find treatments for prion diseases or at least be useful for the goals of medicinal chemistry.

  1. Aerosols transmit prions to immunocompetent and immunodeficient mice.

    Directory of Open Access Journals (Sweden)

    Johannes Haybaeck

    Full Text Available Prions, the agents causing transmissible spongiform encephalopathies, colonize the brain of hosts after oral, parenteral, intralingual, or even transdermal uptake. However, prions are not generally considered to be airborne. Here we report that inbred and crossbred wild-type mice, as well as tga20 transgenic mice overexpressing PrP(C, efficiently develop scrapie upon exposure to aerosolized prions. NSE-PrP transgenic mice, which express PrP(C selectively in neurons, were also susceptible to airborne prions. Aerogenic infection occurred also in mice lacking B- and T-lymphocytes, NK-cells, follicular dendritic cells or complement components. Brains of diseased mice contained PrP(Sc and transmitted scrapie when inoculated into further mice. We conclude that aerogenic exposure to prions is very efficacious and can lead to direct invasion of neural pathways without an obligatory replicative phase in lymphoid organs. This previously unappreciated risk for airborne prion transmission may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories.

  2. Aerosols transmit prions to immunocompetent and immunodeficient mice.

    Science.gov (United States)

    Haybaeck, Johannes; Heikenwalder, Mathias; Klevenz, Britta; Schwarz, Petra; Margalith, Ilan; Bridel, Claire; Mertz, Kirsten; Zirdum, Elizabeta; Petsch, Benjamin; Fuchs, Thomas J; Stitz, Lothar; Aguzzi, Adriano

    2011-01-01

    Prions, the agents causing transmissible spongiform encephalopathies, colonize the brain of hosts after oral, parenteral, intralingual, or even transdermal uptake. However, prions are not generally considered to be airborne. Here we report that inbred and crossbred wild-type mice, as well as tga20 transgenic mice overexpressing PrP(C), efficiently develop scrapie upon exposure to aerosolized prions. NSE-PrP transgenic mice, which express PrP(C) selectively in neurons, were also susceptible to airborne prions. Aerogenic infection occurred also in mice lacking B- and T-lymphocytes, NK-cells, follicular dendritic cells or complement components. Brains of diseased mice contained PrP(Sc) and transmitted scrapie when inoculated into further mice. We conclude that aerogenic exposure to prions is very efficacious and can lead to direct invasion of neural pathways without an obligatory replicative phase in lymphoid organs. This previously unappreciated risk for airborne prion transmission may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories. PMID:21249178

  3. Biochemical Characterization of Prion Strains in Bank Voles

    Directory of Open Access Journals (Sweden)

    Romolo Nonno

    2013-07-01

    Full Text Available Prions exist as different strains exhibiting distinct disease phenotypes. Currently, the identification of prion strains is still based on biological strain typing in rodents. However, it has been shown that prion strains may be associated with distinct PrPSc biochemical types. Taking advantage of the availability of several prion strains adapted to a novel rodent model, the bank vole, we investigated if any prion strain was actually associated with distinctive PrPSc biochemical characteristics and if it was possible to univocally identify strains through PrPSc biochemical phenotypes. We selected six different vole-adapted strains (three human-derived and three animal-derived and analyzed PrPSc from individual voles by epitope mapping of protease resistant core of PrPSc (PrPres and by conformational stability and solubility assay. Overall, we discriminated five out of six prion strains, while two different scrapie strains showed identical PrPSc types. Our results suggest that the biochemical strain typing approach here proposed was highly discriminative, although by itself it did not allow us to identify all prion strains analyzed.

  4. Repetitive immunization enhances the susceptibility of mice to peripherally administered prions.

    Directory of Open Access Journals (Sweden)

    Juliane Bremer

    Full Text Available The susceptibility of humans and animals to prion infections is determined by the virulence of the infectious agent, by genetic modifiers, and by hitherto unknown host and environmental risk factors. While little is known about the latter two, the activation state of the immune system was surmised to influence prion susceptibility. Here we administered prions to mice that were repeatedly immunized by two initial injections of CpG oligodeoxynucleotides followed by repeated injections of bovine serum albumin/alum. Immunization greatly reduced the required dosage of peripherally administered prion inoculum necessary to induce scrapie in 50% of mice. No difference in susceptibility was observed following intracerebral prion challenge. Due to its profound impact onto scrapie susceptibility, the host immune status may determine disease penetrance after low-dose prion exposure, including those that may give rise to iatrogenic and variant Creutzfeldt-Jakob disease.

  5. Clinical characteristics of caroli's disease

    Institute of Scientific and Technical Information of China (English)

    Ozlem Yonem; Yusuf Bayraktar

    2007-01-01

    Caroli's disease is a rare congenital condition characterized by non-obstructive saccular or fusiform dilatation of larger intrahepatic bile ducts. Cholangitis,liver cirrhosis, and cholangiocarcinoma are its potential complications. The diagnosis of Caroli's disease depends on demonstrating that the cystic lesions are in continuity with the biliary tree which can be showed by ultrasonography, computerized tomography, endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography or magnetic resonance cholangiopancreatography. Treatment of Caroli's disease relies on the location of the biliary abnormalities. While localized forms confined to one lobe can be treated with surgery, liver transplantation is the only effective modality for diffuse forms. Although a rare disorder;Caroli's disease should always be considered in the differential diagnosis of chronic cholestasis of unknown cause.

  6. Propagation of prions causing synucleinopathies in cultured cells

    OpenAIRE

    Woerman, AL; StÖhr, J.; Aoyagi, A; Rampersaud, R; Krejciova, Z; Watts, JC; T. Ohyama; Patel, S; Widjaja, K; Oehler, A; Sanders, DW; Diamond, MI; Seeley, WW; Middleton, LT; Gentleman, SM

    2015-01-01

    © 2015, National Academy of Sciences. All rights reserved. Increasingly, evidence argues that many neurodegenerative diseases, including progressive supranuclear palsy (PSP), are caused by prions, which are alternatively folded proteins undergoing self-propagation. In earlier studies, PSP prions were detected by infecting human embryonic kidney (HEK) cells expressing a tau fragment [TauRD(LM)] fused to yellow fluorescent protein (YFP). Here, we report on an improved bioassay using selective p...

  7. Low Copper and High Manganese Levels in Prion Protein Plaques

    OpenAIRE

    Debbie McKenzie; Aiken, Judd M.; Johnson, Christopher J.; P.U.P.A. Gilbert; Mike Abrecht; Baldwin, Katherine L.; Robin E. Russell; Pedersen, Joel A.

    2013-01-01

    Accumulation of aggregates rich in an abnormally folded form of the prion protein characterize the neurodegeneration caused by transmissible spongiform encephalopathies (TSEs). The molecular triggers of plaque formation and neurodegeneration remain unknown, but analyses of TSE-infected brain homogenates and preparations enriched for abnormal prion protein suggest that reduced levels of copper and increased levels of manganese are associated with disease. The objectives of this study were to: ...

  8. The non-octarepeat copper binding site of the prion protein is a key regulator of prion conversion

    Science.gov (United States)

    Giachin, Gabriele; Mai, Phuong Thao; Tran, Thanh Hoa; Salzano, Giulia; Benetti, Federico; Migliorati, Valentina; Arcovito, Alessandro; Longa, Stefano Della; Mancini, Giordano; D'Angelo, Paola; Legname, Giuseppe

    2015-10-01

    The conversion of the prion protein (PrPC) into prions plays a key role in transmissible spongiform encephalopathies. Despite the importance for pathogenesis, the mechanism of prion formation has escaped detailed characterization due to the insoluble nature of prions. PrPC interacts with copper through octarepeat and non-octarepeat binding sites. Copper coordination to the non-octarepeat region has garnered interest due to the possibility that this interaction may impact prion conversion. We used X-ray absorption spectroscopy to study copper coordination at pH 5.5 and 7.0 in human PrPC constructs, either wild-type (WT) or carrying pathological mutations. We show that mutations and pH cause modifications of copper coordination in the non-octarepeat region. In the WT at pH 5.5, copper is anchored to His96 and His111, while at pH 7 it is coordinated by His111. Pathological point mutations alter the copper coordination at acidic conditions where the metal is anchored to His111. By using in vitro approaches, cell-based and computational techniques, we propose a model whereby PrPC coordinating copper with one His in the non-octarepeat region converts to prions at acidic condition. Thus, the non-octarepeat region may act as the long-sought-after prion switch, critical for disease onset and propagation.

  9. Characterisation of new monoclonal antibodies reacting with prions from both human and animal brain tissues

    DEFF Research Database (Denmark)

    Cordes, H.; Bergstrom, A.L.; Ohm, J.;

    2008-01-01

    Post-mortem diagnosis of transmissible spongiform encephalopathies (prion diseases) is primarily based on the detection of a protease resistant, misfolded disease associated isoform (PrP(Sc)) of the prion protein (PrP(C)) on neuronal cells. These methods depend on antibodies directed against PrP(...

  10. Harnessing prions as test agents for the development of broad-range disinfectants

    OpenAIRE

    Wagenführ, Katja; Beekes, Michael

    2012-01-01

    The development of disinfectants with broad-range efficacy against bacteria, viruses, fungi, protozoa and prions constitutes an ongoing challenge. Prions, the causative agents of transmissible spongiform encephalopathies (TSEs) such as Creutzfeldt-Jakob disease (CJD) or its variant (vCJD) rank among the pathogens with the highest resistance to disinfection. Pilot studies have shown that different procedures devised for prion disinfection were also highly effective against microbial pathogens....

  11. Evolutionary Implications of Metal Binding Features in Different Species’ Prion Protein: An Inorganic Point of View

    OpenAIRE

    Diego La Mendola; Enrico Rizzarelli

    2014-01-01

    Prion disorders are a group of fatal neurodegenerative conditions of mammals. The key molecular event in the pathogenesis of such diseases is the conformational conversion of prion protein, PrPC, into a misfolded form rich in β-sheet structure, PrPSc, but the detailed mechanistic aspects of prion protein conversion remain enigmatic. There is uncertainty on the precise physiological function of PrPC in healthy individuals. Several evidences support the notion of its role in copper homeostasis...

  12. B Cell-Specific S1PR1 Deficiency Blocks Prion Dissemination between Secondary Lymphoid Organs

    OpenAIRE

    Mok, S. W.; Proia, R L; Brinkmann, V; Mabbott, N A

    2012-01-01

    Many prion diseases are peripherally acquired (e.g., orally or via lesions to skin or mucous membranes). After peripheral exposure, prions replicate first upon follicular dendritic cells (FDC) in the draining lymphoid tissue before infecting the brain. However, after replication upon FDC within the draining lymphoid tissue, prions are subsequently propagated to most nondraining secondary lymphoid organs (SLO), including the spleen, by a previously underdetermined mechanism. The germinal cente...

  13. A survey and a molecular dynamics study on the (central) hydrophobic region of prion proteins

    OpenAIRE

    Zhang, Jiapu; Wang, Feng

    2014-01-01

    Prion diseases are invariably fatal neurodegenerative diseases that affect humans and animals. Unlike most other amyloid forming neurodegenerative diseases, these can be highly infectious. Prion diseases occur in a variety of species. They include the fatal human neurodegenerative diseases Creutzfeldt-Jakob Disease (CJD), Fatal Familial Insomnia (FFI), Gerstmann-Straussler-Scheinker syndrome (GSS), Kuru, the bovine spongiform encephalopathy (BSE or 'mad-cow' disease) in cattle, the chronic wa...

  14. Autoimmune Inner Ear Disease- A Clinical Viewpoint

    Directory of Open Access Journals (Sweden)

    Amirala Khalessi

    2010-10-01

    Full Text Available Recent developments in medicine have given us a better insight into a group of disorders known as autoimmune diseases. In particular, advances have occurred in our understanding of the Autoimmune Inner Ear Disease (AIED. In this article, the authors review the different postulated theories in the pathogenesis of this disease. The clinical presentation, the available para-clinical diagnostic tools, and the important differential diagnoses will be summarized. The management methods, including steroid therapy, immunosuppressive medications, other biological agents and intra-tympanic injections, will be addressed. Cochlear implantation as a final solution to the advanced stages of the disease, causing total deafness, will also be discussed.

  15. Strain specific resistance to murine scrapie associated with a naturally occurring human prion protein polymorphism at residue 171.

    Directory of Open Access Journals (Sweden)

    James F Striebel

    2011-09-01

    Full Text Available Transmissible spongiform encephalopathies (TSE or prion diseases are neurodegenerative disorders associated with conversion of normal host prion protein (PrP to a misfolded, protease-resistant form (PrPres. Genetic variations of prion protein in humans and animals can alter susceptibility to both familial and infectious prion diseases. The N171S PrP polymorphism is found mainly in humans of African descent, but its low incidence has precluded study of its possible influence on prion disease. Similar to previous experiments of others, for laboratory studies we created a transgenic model expressing the mouse PrP homolog, PrP-170S, of human PrP-171S. Since PrP polymorphisms can vary in their effects on different TSE diseases, we tested these mice with four different strains of mouse-adapted scrapie. Whereas 22L and ME7 scrapie strains induced typical clinical disease, neuropathology and accumulation of PrPres in all transgenic mice at 99-128 average days post-inoculation, strains RML and 79A produced clinical disease and PrPres formation in only a small subset of mice at very late times. When mice expressing both PrP-170S and PrP-170N were inoculated with RML scrapie, dominant-negative inhibition of disease did not occur, possibly because interaction of strain RML with PrP-170S was minimal. Surprisingly, in vitro PrP conversion using protein misfolding cyclic amplification (PMCA, did not reproduce the in vivo findings, suggesting that the resistance noted in live mice might be due to factors or conditions not present in vitro. These findings suggest that in vivo conversion of PrP-170S by RML and 79A scrapie strains was slow and inefficient. PrP-170S mice may be an example of the conformational selection model where the structure of some prion strains does not favor interactions with PrP molecules expressing certain polymorphisms.

  16. Soil humic substances hinder the propagation of prions

    Science.gov (United States)

    Leita, Liviana; Giachin, Gabriele; Margon, Alja; Narkiewicz, Joanna; Legname, Giuseppe

    2013-04-01

    Prions are infectious pathogens causing fatal neurodegenerative disorders, known as transmissible spongiform encephalopathies (TSEs), or prion diseases, which affect different mammalian species. TSEs include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in mule deer, elk, and moose (cervids), and Creutzfeldt-Jakob disease (CJD) in humans. The prominent, if not only, component of prions is a misfolded conformer (PrPSc) of a constitutive sialoglycoprotein, the cellular prion protein (PrPC). A notable feature of prion diseases is horizontal transmission between grazing animals, implying that contaminated soil may serve to propagate the disease. In this respect, it has been reported that grazing animals ingest from tens to hundreds grams of soil per day, either incidentally through the diet, or deliberately in answering salt needs, and that mule deer can develop CWD after grazing in locations that previously housed infected animals. Prions may enter the environment through different routes, including animal excreta and secreta which mainly contribute to soil contamination. Recent studies have proven that prions can be retained in soil, which could act as a carrier of infectivity even several years after the contamination. However, within the large spread of potentially infected lands, prion diseases have become endemic only in geographically limited regions. The reasons for this geographical distribution remain unknown, but it suggests a role of the different kinds of soil in either enhancing or attenuating prion infectivity. The extent of prion transmission from the contaminated environment is unknown. Several studies have tried to address the issue of prion interaction with soil, but, at the present, different approaches show several drawbacks and technical difficulties, as soil is a complex, multi-component system of both mineral and organic interacting substances. Most research has focused on the adsorption

  17. De novo generation of prion strains

    OpenAIRE

    Colby, David W.; Prusiner, Stanley B.

    2011-01-01

    Prions are self-replicating proteins that cause neurodegenerative disorders such as “mad cow” disease. These misprocessed protein conformations accumulate in the central nervous system, causing spongiform changes in the brain and eventually death. Since the inception of the protein-only hypothesis — which posits that misfolded proteins are the infectious agents that cause these diseases — researchers seeking to generate infectious proteins from defined components in the laboratory have had va...

  18. Unusual cerebral vascular prion protein amyloid distribution in scrapie-infected transgenic mice expressing anchorless prion protein

    OpenAIRE

    Rangel, Alejandra; Race, Brent; Klingeborn, Mikael; Striebel, James; Chesebro, Bruce

    2013-01-01

    Background In some prion diseases, misfolded aggregated protease-resistant prion protein (PrPres) is found in brain as amyloid, which can cause cerebral amyloid angiopathy. Small diffusible precursors of PrPres amyloid might flow with brain interstitial fluid (ISF), possibly accounting for the perivascular and intravascular distribution of PrPres amyloid. We previously reported that PrPres amyloid in scrapie-infected transgenic mice appeared to delay clearance of microinjected brain ISF trace...

  19. Clinical Scenarios in Chronic Kidney Disease: Cystic Renal Diseases.

    Science.gov (United States)

    Meola, Mario; Samoni, Sara; Petrucci, Ilaria

    2016-01-01

    Cysts are frequently found in chronic kidney disease (CKD) and they have a different prognostic significance depending on the clinical context. Simple solitary parenchymal cysts and peripelvic cysts are very common and they have no clinical significance. At US, simple cyst appears as a round anechoic pouch with regular and thin profiles. On the other hand, hereditary polycystic disease is a frequent cause of CKD in children and adults. Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are the best known cystic hereditary diseases. ADPKD and ARPKD show a diffused cystic degeneration with cysts of different diameters derived from tubular epithelium. Medullary cystic disease may be associated with tubular defects, acidosis and lithiasis and can lead to CKD. Acquired cystic kidney disease, finally, is secondary to progressive structural end-stage kidney remodelling and may be associated with renal cell carcinoma. PMID:27169740

  20. Follicular dendritic cell-specific prion protein (PrP) expression alone is sufficient to sustain prion infection in the spleen.

    Science.gov (United States)

    McCulloch, Laura; Brown, Karen L; Bradford, Barry M; Hopkins, John; Bailey, Mick; Rajewsky, Klaus; Manson, Jean C; Mabbott, Neil A

    2011-12-01

    Prion diseases are characterised by the accumulation of PrP(Sc), an abnormally folded isoform of the cellular prion protein (PrP(C)), in affected tissues. Following peripheral exposure high levels of prion-specific PrP(Sc) accumulate first upon follicular dendritic cells (FDC) in lymphoid tissues before spreading to the CNS. Expression of PrP(C) is mandatory for cells to sustain prion infection and FDC appear to express high levels. However, whether FDC actively replicate prions or simply acquire them from other infected cells is uncertain. In the attempts to-date to establish the role of FDC in prion pathogenesis it was not possible to dissociate the Prnp expression of FDC from that of the nervous system and all other non-haematopoietic lineages. This is important as FDC may simply acquire prions after synthesis by other infected cells. To establish the role of FDC in prion pathogenesis transgenic mice were created in which PrP(C) expression was specifically "switched on" or "off" only on FDC. We show that PrP(C)-expression only on FDC is sufficient to sustain prion replication in the spleen. Furthermore, prion replication is blocked in the spleen when PrP(C)-expression is specifically ablated only on FDC. These data definitively demonstrate that FDC are the essential sites of prion replication in lymphoid tissues. The demonstration that Prnp-ablation only on FDC blocked splenic prion accumulation without apparent consequences for FDC status represents a novel opportunity to prevent neuroinvasion by modulation of PrP(C) expression on FDC. PMID:22144895

  1. Follicular dendritic cell-specific prion protein (PrP expression alone is sufficient to sustain prion infection in the spleen.

    Directory of Open Access Journals (Sweden)

    Laura McCulloch

    2011-12-01

    Full Text Available Prion diseases are characterised by the accumulation of PrP(Sc, an abnormally folded isoform of the cellular prion protein (PrP(C, in affected tissues. Following peripheral exposure high levels of prion-specific PrP(Sc accumulate first upon follicular dendritic cells (FDC in lymphoid tissues before spreading to the CNS. Expression of PrP(C is mandatory for cells to sustain prion infection and FDC appear to express high levels. However, whether FDC actively replicate prions or simply acquire them from other infected cells is uncertain. In the attempts to-date to establish the role of FDC in prion pathogenesis it was not possible to dissociate the Prnp expression of FDC from that of the nervous system and all other non-haematopoietic lineages. This is important as FDC may simply acquire prions after synthesis by other infected cells. To establish the role of FDC in prion pathogenesis transgenic mice were created in which PrP(C expression was specifically "switched on" or "off" only on FDC. We show that PrP(C-expression only on FDC is sufficient to sustain prion replication in the spleen. Furthermore, prion replication is blocked in the spleen when PrP(C-expression is specifically ablated only on FDC. These data definitively demonstrate that FDC are the essential sites of prion replication in lymphoid tissues. The demonstration that Prnp-ablation only on FDC blocked splenic prion accumulation without apparent consequences for FDC status represents a novel opportunity to prevent neuroinvasion by modulation of PrP(C expression on FDC.

  2. Early Cytokine Elevation, PrPres Deposition, and Gliosis in Mouse Scrapie: No Effect on Disease by Deletion of Cytokine Genes IL-12p40 and IL-12p35

    OpenAIRE

    Tribouillard-Tanvier, Déborah; Race, Brent; Striebel, James F.; Carroll, James A.; Phillips, Katie; Chesebro, Bruce

    2012-01-01

    Neurodegenerative diseases are typically associated with an activation of glia and an increased level of cytokines. In our previous studies of prion disease, the cytokine response in the brains of clinically sick scrapie-infected mice was restricted to a small group of cytokines, of which IL-12p40, CCL2, and CXCL10 were present at the highest levels. The goal of our current research was to determine the relationship between cytokine responses, gliosis, and neuropathology during prion disease....

  3. The clinical spectrum of hexosaminidase deficiency diseases.

    Science.gov (United States)

    Johnson, W G

    1981-11-01

    Hexosaminidase deficiency diseases or GM2-gangliosidoses were originally described as infantile encephalopathies. Recently, hexosaminidase deficiencies have been found with different phenotypes, including juvenile and adult encephalopathies, cerebellar ataxias, and motor neuron diseases. Individual cases have resembled Ramsey-Hunt syndrome, olivopontocerebellar ataxia, Friedreich ataxia, amyotrophic lateral sclerosis, Kugelberg-Welander disease, Fazio-Londe disease, and Charcot-Marie-Tooth disease. Tremor, dystonia, spastic paresis, and psychosis have been seen. Since few diagnosable causes for these system atrophies are known, these patients should be tested for hexosaminidase deficiency. These recessive disorders fit a multiple loci/multiple alleles genetic scheme, and a clinical genetic classification is presented.

  4. Clinical case of Hailey-Hailey disease

    Directory of Open Access Journals (Sweden)

    Karpova E.N.

    2015-09-01

    Full Text Available The study presents a relatively rare case of dermatosis. It is familial benign chronic vesicular fever (Hailey-Hailey disease in a 58-years old female patient which is inherited as an autosomal dominant mode. The data about etiology, pathogenesis, clinical picture and differential diagnosis were summarized. The main ways of treatment of the disease are described.

  5. Clinical case of Hailey-Hailey disease

    OpenAIRE

    Karpova E.N.; Schneider D.A.; Bobko N.K.

    2015-01-01

    The study presents a relatively rare case of dermatosis. It is familial benign chronic vesicular fever (Hailey-Hailey disease) in a 58-years old female patient which is inherited as an autosomal dominant mode. The data about etiology, pathogenesis, clinical picture and differential diagnosis were summarized. The main ways of treatment of the disease are described.

  6. Diagnostic approaches for viruses and prions in stem cell banks

    International Nuclear Information System (INIS)

    Some stem cell lines may contain an endogenous virus or can be contaminated with exogenous viruses (even of animal origin) and may secrete viral particles or express viral antigens on their surface. Moreover, certain biotechnological products (e.g. bovine fetal serum, murine feeder cells) may contain prion particles. Viral and prion contamination of cell cultures and 'feeder' cells, which is a common risk in all biotechnological products derived from the cell lines, is the most challenging and potentially serious outcome to address, due to the difficulty involved in virus and prion detection and the potential to cause serious disease in recipients of these cell products. Stem cell banks should introduce adequate quality assurance programs like the microbiological control program and can provide researchers with valuable support in the standardization and safety of procedures and protocols used for the viral and prion testing and in validation programs to assure the quality and safety of the cells

  7. Intraepithelial and interstitial deposition of pathological prion protein in kidneys of scrapie-affected sheep.

    Directory of Open Access Journals (Sweden)

    Ciriaco Ligios

    Full Text Available Prions have been documented in extra-neuronal and extra-lymphatic tissues of humans and various ruminants affected by Transmissible Spongiform Encephalopathy (TSE. The presence of prion infectivity detected in cervid and ovine blood tempted us to reason that kidney, the organ filtrating blood derived proteins, may accumulate disease associated PrP(Sc. We collected and screened kidneys of experimentally, naturally scrapie-affected and control sheep for renal deposition of PrP(Sc from distinct, geographically separated flocks. By performing Western blot, PET blot analysis and immunohistochemistry we found intraepithelial (cortex, medulla and papilla and occasional interstitial (papilla deposition of PrP(Sc in kidneys of scrapie-affected sheep. Interestingly, glomerula lacked detectable signals indicative of PrP(Sc. PrP(Sc was also detected in kidneys of subclinical sheep, but to significantly lower degree. Depending on the stage of the disease the incidence of PrP(Sc in kidney varied from approximately 27% (subclinical to 73.6% (clinical in naturally scrapie-affected sheep. Kidneys from flocks without scrapie outbreak were devoid of PrP(Sc. Here we demonstrate unexpectedly frequent deposition of high levels of PrP(Sc in ovine kidneys of various flocks. Renal deposition of PrP(Sc is likely to be a pre-requisite enabling prionuria, a possible co-factor of horizontal prion-transmission in sheep.

  8. Clinical Features of Interstitial Lung Diseases

    OpenAIRE

    Lim, Gune-Il; Lee, Kwang Hee; Jeong, Seong Whan; Uh, Soo-taek; Jin, So Young; Lee, Dong Hwa; Park, Jai Soung; Choi, Deuk Lin; Kang, Chang Hee; Park, Choon Sik

    1996-01-01

    Objectives Interstitial lung diseases (ILD) are heterogenous groups of disorders that involve the interstitium of the lung. Lung biopsy is mandatory in most cases of ILD for diagnosis. In Korea, a few clinical data about ILD were analyzed on the basis of pathologic proof. Thus, we analysed the clinical profiles of patients with ILD who had lung biopsy in a tertiary university hospital. Methods Clinical and pathologic data concerning 100 patients who had open lung biopsy (OLB) and/or transbron...

  9. The Role of Functional Prion-Like Proteins in the Persistence of Memory.

    Science.gov (United States)

    Si, Kausik; Kandel, Eric R

    2016-01-01

    Prions are a self-templating amyloidogenic state of normal cellular proteins, such as prion protein (PrP). They have been identified as the pathogenic agents, contributing to a number of diseases of the nervous system. However, the discovery that the neuronal RNA-binding protein, cytoplasmic polyadenylation element-binding protein (CPEB), has a prion-like state that is involved in the stabilization of memory raised the possibility that prion-like proteins can serve normal physiological functions in the nervous system. Here, we review recent experimental evidence of prion-like properties of neuronal CPEB in various organisms and propose a model of how the prion-like state may stabilize memory. PMID:27037416

  10. Molecular modeling of the conformational dynamics of the cellular prion protein

    Science.gov (United States)

    Nguyen, Charles; Colling, Ian; Bartz, Jason; Soto, Patricia

    2014-03-01

    Prions are infectious agents responsible for transmissible spongiform encephalopathies (TSEs), a type of fatal neurodegenerative disease in mammals. Prions propagate biological information by conversion of the non-pathological version of the prion protein to the infectious conformation, PrPSc. A wealth of knowledge has shed light on the nature and mechanism of prion protein conversion. In spite of the significance of this problem, we are far from fully understanding the conformational dynamics of the cellular isoform. To remedy this situation we employ multiple biomolecular modeling techniques such as docking and molecular dynamics simulations to map the free energy landscape and determine what specific regions of the prion protein are most conductive to binding. The overall goal is to characterize the conformational dynamics of the cell form of the prion protein, PrPc, to gain insight into inhibition pathways against misfolding. NE EPSCoR FIRST Award to Patricia Soto.

  11. Incunabular immunological events in prion trafficking.

    Science.gov (United States)

    Michel, Brady; Meyerett-Reid, Crystal; Johnson, Theodore; Ferguson, Adam; Wyckoff, Christy; Pulford, Bruce; Bender, Heather; Avery, Anne; Telling, Glenn; Dow, Steven; Zabel, Mark D

    2012-01-01

    While prions probably interact with the innate immune system immediately following infection, little is known about this initial confrontation. Here we investigated incunabular events in lymphotropic and intranodal prion trafficking by following highly enriched, fluorescent prions from infection sites to draining lymph nodes. We detected biphasic lymphotropic transport of prions from the initial entry site upon peripheral prion inoculation. Prions arrived in draining lymph nodes cell autonomously within two hours of intraperitoneal administration. Monocytes and dendritic cells (DCs) required Complement for optimal prion delivery to lymph nodes hours later in a second wave of prion trafficking. B cells constituted the majority of prion-bearing cells in the mediastinal lymph node by six hours, indicating intranodal prion reception from resident DCs or subcapsulary sinus macrophages or directly from follicular conduits. These data reveal novel, cell autonomous prion lymphotropism, and a prominent role for B cells in intranodal prion movement. PMID:22679554

  12. Characterization of 2 '-fluoro-RNA aptamers that bind preferentially to disease-associated conformations of prion protein and inhibit conversion

    OpenAIRE

    Rhie, A.; Kirby, L.; Sayer, N.; Wellesley, R.; Disterer, P; Sylvester, I; Gill, A; Hope, J.; James, W.; Tahiri-Alaoui, A

    2003-01-01

    We have isolated artificial ligands or aptamers for infectious prions in order to investigate conformational aspects of prion pathogenesis. The aptamers are 2'-fluoro-modified RNA produced by in vitro selection from a large, randomized library. One of these ligands (aptamer SAF-93) had more than 10-fold higher affinity for PrPSc than for recombinant PrPC and inhibited the accumulation of PrPres in near physiological cell-free conversion assay. To understand the molecular basis of these proper...

  13. [Functions of prion protein PrPc].

    Science.gov (United States)

    Cazaubon, Sylvie; Viegas, Pedro; Couraud, Pierre-Olivier

    2007-01-01

    It is now well established that both normal and pathological (or scrapie) isoforms of prion protein, PrPc and PrPsc respectively, are involved in the development and progression of various forms of neurodegenerative diseases, including scrapie in sheep, bovine spongiform encephalopathy (or "mad cow disease") and Creutzfeldt-Jakob disease in human, collectively known as prion diseases. The protein PrPc is highly expressed in the central nervous system in neurons and glial cells, and also present in non-brain cells, such as immune cells or epithelial and endothelial cells. Identification of the physiological functions of PrPc in these different cell types thus appears crucial for understanding the progression of prion diseases. Recent studies highlighted several major roles for PrPc that may be considered in two major domains : (1) cell survival (protection against oxidative stress and apoptosis) and (2) cell adhesion. In association with cell adhesion, distinct functions of PrPc were observed, depending on cell types : neuronal differentiation, epithelial and endothelial barrier integrity, transendothelial migration of monocytes, T cell activation. These observations suggest that PrPc functions may be particularly relevant to cellular stress, as well as inflammatory or infectious situations. PMID:17875293

  14. Transmission barriers for bovine ovine, and human prions in transgenic mice

    OpenAIRE

    Van Scott, Michael R.; Peretz, David; Nguyen, Hoang-Oanh B.; Stephen J DeArmond; Prusiner, Stanley B.

    2005-01-01

    Transgenic (Tg) mice expressing full-length bovine prion protein (BoPrP) serially propagate bovine spongiform encephalopathy (BSE) prions without posing a transmission barrier. These mice also posed no transmission barrier for Suffolk sheep scrapie prions, suggesting that cattle may be highly susceptible to some sheep scrapie strains. Tg(BoPrP) mice were also found to be susceptible to prions from humans with variant Creutzfeldt-Jakob disease (CJD); on second passage in Tg(BoPrP) mice, the in...

  15. Low Copper and High Manganese Levels in Prion Protein Plaques

    Directory of Open Access Journals (Sweden)

    Debbie McKenzie

    2013-02-01

    Full Text Available Accumulation of aggregates rich in an abnormally folded form of the prion protein characterize the neurodegeneration caused by transmissible spongiform encephalopathies (TSEs. The molecular triggers of plaque formation and neurodegeneration remain unknown, but analyses of TSE-infected brain homogenates and preparations enriched for abnormal prion protein suggest that reduced levels of copper and increased levels of manganese are associated with disease. The objectives of this study were to: (1 assess copper and manganese levels in healthy and TSE-infected Syrian hamster brain homogenates; (2 determine if the distribution of these metals can be mapped in TSE-infected brain tissue using X-ray photoelectron emission microscopy (X-PEEM with synchrotron radiation; and (3 use X-PEEM to assess the relative amounts of copper and manganese in prion plaques in situ. In agreement with studies of other TSEs and species, we found reduced brain levels of copper and increased levels of manganese associated with disease in our hamster model. We also found that the in situ levels of these metals in brainstem were sufficient to image by X-PEEM. Using immunolabeled prion plaques in directly adjacent tissue sections to identify regions to image by X-PEEM, we found a statistically significant relationship of copper-manganese dysregulation in prion plaques: copper was depleted whereas manganese was enriched. These data provide evidence for prion plaques altering local transition metal distribution in the TSE-infected central nervous system.

  16. Low copper and high manganese levels in prion protein plaques.

    Science.gov (United States)

    Johnson, Christopher J; Gilbert, P U P A; Abrecht, Mike; Baldwin, Katherine L; Russell, Robin E; Pedersen, Joel A; Aiken, Judd M; McKenzie, Debbie

    2013-02-01

    Accumulation of aggregates rich in an abnormally folded form of the prion protein characterize the neurodegeneration caused by transmissible spongiform encephalopathies (TSEs). The molecular triggers of plaque formation and neurodegeneration remain unknown, but analyses of TSE-infected brain homogenates and preparations enriched for abnormal prion protein suggest that reduced levels of copper and increased levels of manganese are associated with disease. The objectives of this study were to: (1) assess copper and manganese levels in healthy and TSE-infected Syrian hamster brain homogenates; (2) determine if the distribution of these metals can be mapped in TSE-infected brain tissue using X-ray photoelectron emission microscopy (X-PEEM) with synchrotron radiation; and (3) use X-PEEM to assess the relative amounts of copper and manganese in prion plaques in situ. In agreement with studies of other TSEs and species, we found reduced brain levels of copper and increased levels of manganese associated with disease in our hamster model. We also found that the in situ levels of these metals in brainstem were sufficient to image by X-PEEM. Using immunolabeled prion plaques in directly adjacent tissue sections to identify regions to image by X-PEEM, we found a statistically significant relationship of copper-manganese dysregulation in prion plaques: copper was depleted whereas manganese was enriched. These data provide evidence for prion plaques altering local transition metal distribution in the TSE-infected central nervous system.

  17. Low copper and high manganese levels in prion protein plaques

    Science.gov (United States)

    Johnson, Christopher J.; Gilbert, P.U.P.A.; Abrecth, Mike; Baldwin, Katherine L.; Russell, Robin E.; Pedersen, Joel A.; McKenzie, Debbie

    2013-01-01

    Accumulation of aggregates rich in an abnormally folded form of the prion protein characterize the neurodegeneration caused by transmissible spongiform encephalopathies (TSEs). The molecular triggers of plaque formation and neurodegeneration remain unknown, but analyses of TSE-infected brain homogenates and preparations enriched for abnormal prion protein suggest that reduced levels of copper and increased levels of manganese are associated with disease. The objectives of this study were to: (1) assess copper and manganese levels in healthy and TSE-infected Syrian hamster brain homogenates; (2) determine if the distribution of these metals can be mapped in TSE-infected brain tissue using X-ray photoelectron emission microscopy (X-PEEM) with synchrotron radiation; and (3) use X-PEEM to assess the relative amounts of copper and manganese in prion plaques in situ. In agreement with studies of other TSEs and species, we found reduced brain levels of copper and increased levels of manganese associated with disease in our hamster model. We also found that the in situ levels of these metals in brainstem were sufficient to image by X-PEEM. Using immunolabeled prion plaques in directly adjacent tissue sections to identify regions to image by X-PEEM, we found a statistically significant relationship of copper-manganese dysregulation in prion plaques: copper was depleted whereas manganese was enriched. These data provide evidence for prion plaques altering local transition metal distribution in the TSE-infected central nervous system.

  18. Reduction of prion infectivity in packed red blood cells

    International Nuclear Information System (INIS)

    The link between a new variant form of Creutzfeldt-Jakob disease (vCJD) and the consumption of prion contaminated cattle meat as well as recent findings showing that vCJD can be transmitted by blood transfusion have raised public health concerns. Currently, a reliable test to identify prions in blood samples is not available. The purpose of this study was to evaluate the possibility to remove scrapie prion protein (PrPSc) and infectivity from red blood cell (RBC) suspensions by a simple washing procedure using a cell separation and washing device. The extent of prion removal was assessed by Western blot, PMCA and infectivity bioassays. Our results revealed a substantial removal of infectious prions (≥3 logs of infectivity) by all techniques used. These data suggest that a significant amount of infectivity present in RBC preparations can be removed by a simple washing procedure. This technology may lead to increased safety of blood products and reduce the risk of further propagation of prion diseases.

  19. Prion remains infectious after passage through digestive system of American crows (Corvus brachyrhynchos.

    Directory of Open Access Journals (Sweden)

    Kurt C VerCauteren

    Full Text Available Avian scavengers, such as American crows (Corvus brachyrhynchos, have potential to translocate infectious agents (prions of transmissible spongiform encephalopathy (TSE diseases including chronic wasting disease, scrapie, and bovine spongiform encephalopathy. We inoculated mice with fecal extracts obtained from 20 American crows that were force-fed material infected with RML-strain scrapie prions. These mice all evinced severe neurological dysfunction 196-231 d postinoculation (x =198; 95% CI: 210-216 and tested positive for prion disease. Our results suggest a large proportion of crows that consume prion-positive tissue are capable of passing infectious prions in their feces (ˆp=1.0; 95% CI: 0.8-1.0. Therefore, this common, migratory North American scavenger could play a role in the geographic spread of TSE diseases.

  20. C1q binding and complement activation by prions and amyloids.

    Science.gov (United States)

    Sim, Robert B; Kishore, Uday; Villiers, Christian L; Marche, Patrice N; Mitchell, Daniel A

    2007-01-01

    C1q binds to many non-self and altered-self-materials. These include microorganisms, immune complexes, apoptotic and necrotic cells and their breakdown products, and amyloids. C1q binding to amyloid fibrils found as extracellular deposits in tissues, and subsequent complement activation are involved in the pathology of several amyloid diseases, such as Alzheimer's disease. Prion diseases, such as scrapie also involve formation of amyloid by polymerization of the host prion protein (PrP). Complement activation is likely to contribute to neuronal damage in the end stages of prion diseases, but is also thought to participate in the initial infection, dissemination and replication stages. Infectious prion particles are likely to bind C1q and activate the complement system. Bound complement proteins may then influence the uptake and transport of prion particles by dendritic cells (DCs) and their subsequent proliferation at sites such as follicular DCs. PMID:17544820

  1. Incunabular Immunological Events in Prion Trafficking

    OpenAIRE

    Michel, Brady; Meyerett-Reid, Crystal; Johnson, Theodore; Ferguson, Adam; Wyckoff, Christy; Pulford, Bruce; Bender, Heather; Avery, Anne; Telling, Glenn; Dow, Steven; Zabel, Mark D.

    2012-01-01

    While prions probably interact with the innate immune system immediately following infection, little is known about this initial confrontation. Here we investigated incunabular events in lymphotropic and intranodal prion trafficking by following highly enriched, fluorescent prions from infection sites to draining lymph nodes. We detected biphasic lymphotropic transport of prions from the initial entry site upon peripheral prion inoculation. Prions arrived in draining lymph nodes cell autonomo...

  2. Pin1 and neurodegeneration: a new player for prion disorders?

    Directory of Open Access Journals (Sweden)

    Elisa Isopi

    2015-07-01

    Full Text Available Pin1 is a peptidyl-prolyl isomerase that catalyzes the cis/trans conversion of phosphorylated proteins at serine or threonine residues which precede a proline. The peptidyl-prolyl isomerization induces a conformational change of the proteins involved in cell signaling process. Pin1 dysregulation has been associated with some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease. Proline-directed phosphorylation is a common regulator of these pathologies and a recent work showed that it is also involved in prion disorders. In fact, prion protein phosphorylation at the Ser-43-Pro motif induces prion protein conversion into a disease-associated form. Furthermore, phosphorylation at Ser-43-Pro has been observed to increase in the cerebral spinal fluid of sporadic Creutzfeldt-Jakob Disease patients. These findings provide new insights into the pathogenesis of prion disorders, suggesting Pin1 as a potential new player in the disease. In this paper, we review the mechanisms underlying Pin1 involvement in the aforementioned neurodegenerative pathologies focusing on the potential role of Pin1 in prion disorders.

  3. Prion protein accumulation in lipid rafts of mouse aging brain.

    Directory of Open Access Journals (Sweden)

    Federica Agostini

    Full Text Available The cellular form of the prion protein (PrP(C is a normal constituent of neuronal cell membranes. The protein misfolding causes rare neurodegenerative disorders known as transmissible spongiform encephalopathies or prion diseases. These maladies can be sporadic, genetic or infectious. Sporadic prion diseases are the most common form mainly affecting aging people. In this work, we investigate the biochemical environment in which sporadic prion diseases may develop, focusing our attention on the cell membrane of neurons in the aging brain. It is well established that with aging the ratio between the most abundant lipid components of rafts undergoes a major change: while cholesterol decreases, sphingomyelin content rises. Our results indicate that the aging process modifies the compartmentalization of PrP(C. In old mice, this change favors PrP(C accumulation in detergent-resistant membranes, particularly in hippocampi. To confirm the relationship between lipid content changes and PrP(C translocation into detergent-resistant membranes (DRMs, we looked at PrP(C compartmentalization in hippocampi from acid sphingomyelinase (ASM knockout (KO mice and synaptosomes enriched in sphingomyelin. In the presence of high sphingomyelin content, we observed a significant increase of PrP(C in DRMS. This process is not due to higher levels of total protein and it could, in turn, favor the onset of sporadic prion diseases during aging as it increases the PrP intermolecular contacts into lipid rafts. We observed that lowering sphingomyelin in scrapie-infected cells by using fumonisin B1 led to a 50% decrease in protease-resistant PrP formation. This may suggest an involvement of PrP lipid environment in prion formation and consequently it may play a role in the onset or development of sporadic forms of prion diseases.

  4. Clinical presentation of adult coeliac disease.

    LENUS (Irish Health Repository)

    Tajuddin, T

    2012-02-01

    The mode of presentation of coeliac disease has been changing to more atypical or silent disease. Few studies described the clinical presentation of adult coeliac disease in Ireland in recent years. We retrospectively collected the clinical data for all patients who had a diagnosis of coeliac disease made in our centre between January 07 and December 08. Forty seven adults, predominantly females (n = 30), had a confirmed diagnosis of coeliac disease made during the study period. In our patient cohort, the presenting symptom was diarrhoea in 19 (40%) patients, while 16 patients (34%) did not have any G.I. symptoms, 10 (21%) presented with anaemia. Females presented at a significantly younger age compared to males, with median ages at diagnosis of 44.5 and 57 years, respectively (p = 0.04). Females also presented more commonly with non G.I. symptoms (p = 0.07). The reasons behind this gender difference need further study.

  5. Prion Protein Self Interactions; a gateway to novel therapeutic strategies?

    NARCIS (Netherlands)

    Rigter, A.; Langeveld, J.P.M.; Zijderveld, van F.G.; Bossers, A.

    2010-01-01

    Transmissible spongiform encephalopathies (TSEs) or prion diseases are fatal neurodegenerative disorders and include among others Creutzfeldt–Jakob disease in humans, bovine spongiform encephalopathy (BSE) in cattle, and scrapie in sheep. The central event in disease development in TSEs is the refol

  6. A direct assessment of human prion adhered to steel wire using real-time quaking-induced conversion.

    Science.gov (United States)

    Mori, Tsuyoshi; Atarashi, Ryuichiro; Furukawa, Kana; Takatsuki, Hanae; Satoh, Katsuya; Sano, Kazunori; Nakagaki, Takehiro; Ishibashi, Daisuke; Ichimiya, Kazuko; Hamada, Masahisa; Nakayama, Takehisa; Nishida, Noriyuki

    2016-01-01

    Accidental transmission of prions during neurosurgery has been reported as a consequence of re-using contaminated surgical instruments. Several decontamination methods have been studied using the 263K-hamster prion; however, no studies have directly evaluated human prions. A newly developed in vitro amplification system, designated real-time quaking-induced conversion (RT-QuIC), has allowed the activity of abnormal prion proteins to be assessed within a few days. RT-QuIC using human recombinant prion protein (PrP) showed high sensitivity for prions as the detection limit of our assay was estimated as 0.12 fg of active prions. We applied this method to detect human prion activity on stainless steel wire. When we put wires contaminated with human Creutzfeldt-Jakob disease brain tissue directly into the test tube, typical PrP-amyloid formation was observed within 48 hours, and we could detect the activity of prions at 50% seeding dose on the wire from 10(2.8) to 10(5.8) SD50. Using this method, we also confirmed that the seeding activities on the wire were removed following treatment with NaOH. As seeding activity closely correlated with the infectivity of prions using the bioassay, this wire-QuIC assay will be useful for the direct evaluation of decontamination methods for human prions. PMID:27112110

  7. Sensitive, Preclinical Detection of Prions in Brain by nanospray liquid chromatography/tandem mass spectrometry

    Science.gov (United States)

    More sensitive detection of prions in brain is important because it would allow early detection of disease in young animals and assure a safer food supply. We quantitated the amount of proteinase K-resistant prion protein (PrP 27-30) by use of nano-scale liquid chromatography coupled to a tandem ma...

  8. Spontaneous generation of mammalian prions

    OpenAIRE

    Edgeworth, Julie A.; Gros, Nathalie; Alden, Jack; Joiner, Susan; Wadsworth, Jonathan D. F.; Linehan, Jackie; Brandner, Sebastian; Jackson, Graham S.; Weissmann, Charles; Collinge, John

    2010-01-01

    Prions are transmissible agents that cause lethal neurodegeneration in humans and other mammals. Prions bind avidly to metal surfaces such as steel wires and, when surface-bound, can initiate infection of brain or cultured cells with remarkable efficiency. While investigating the properties of metal-bound prions by using the scrapie cell assay to measure infectivity, we observed, at low frequency, positive assay results in control groups in which metal wires had been coated with uninfected mo...

  9. Yeast prions form infectious amyloid inclusion bodies in bacteria

    Directory of Open Access Journals (Sweden)

    Espargaró Alba

    2012-06-01

    Full Text Available Abstract Background Prions were first identified as infectious proteins associated with fatal brain diseases in mammals. However, fungal prions behave as epigenetic regulators that can alter a range of cellular processes. These proteins propagate as self-perpetuating amyloid aggregates being an example of structural inheritance. The best-characterized examples are the Sup35 and Ure2 yeast proteins, corresponding to [PSI+] and [URE3] phenotypes, respectively. Results Here we show that both the prion domain of Sup35 (Sup35-NM and the Ure2 protein (Ure2p form inclusion bodies (IBs displaying amyloid-like properties when expressed in bacteria. These intracellular aggregates template the conformational change and promote the aggregation of homologous, but not heterologous, soluble prionogenic molecules. Moreover, in the case of Sup35-NM, purified IBs are able to induce different [PSI+] phenotypes in yeast, indicating that at least a fraction of the protein embedded in these deposits adopts an infectious prion fold. Conclusions An important feature of prion inheritance is the existence of strains, which are phenotypic variants encoded by different conformations of the same polypeptide. We show here that the proportion of infected yeast cells displaying strong and weak [PSI+] phenotypes depends on the conditions under which the prionogenic aggregates are formed in E. coli, suggesting that bacterial systems might become useful tools to generate prion strain diversity.

  10. A Neuronal Culture System to Detect Prion Synaptotoxicity.

    Science.gov (United States)

    Fang, Cheng; Imberdis, Thibaut; Garza, Maria Carmen; Wille, Holger; Harris, David A

    2016-05-01

    Synaptic pathology is an early feature of prion as well as other neurodegenerative diseases. Although the self-templating process by which prions propagate is well established, the mechanisms by which prions cause synaptotoxicity are poorly understood, due largely to the absence of experimentally tractable cell culture models. Here, we report that exposure of cultured hippocampal neurons to PrPSc, the infectious isoform of the prion protein, results in rapid retraction of dendritic spines. This effect is entirely dependent on expression of the cellular prion protein, PrPC, by target neurons, and on the presence of a nine-amino acid, polybasic region at the N-terminus of the PrPC molecule. Both protease-resistant and protease-sensitive forms of PrPSc cause dendritic loss. This system provides new insights into the mechanisms responsible for prion neurotoxicity, and it provides a platform for characterizing different pathogenic forms of PrPSc and testing potential therapeutic agents. PMID:27227882

  11. A Neuronal Culture System to Detect Prion Synaptotoxicity.

    Directory of Open Access Journals (Sweden)

    Cheng Fang

    2016-05-01

    Full Text Available Synaptic pathology is an early feature of prion as well as other neurodegenerative diseases. Although the self-templating process by which prions propagate is well established, the mechanisms by which prions cause synaptotoxicity are poorly understood, due largely to the absence of experimentally tractable cell culture models. Here, we report that exposure of cultured hippocampal neurons to PrPSc, the infectious isoform of the prion protein, results in rapid retraction of dendritic spines. This effect is entirely dependent on expression of the cellular prion protein, PrPC, by target neurons, and on the presence of a nine-amino acid, polybasic region at the N-terminus of the PrPC molecule. Both protease-resistant and protease-sensitive forms of PrPSc cause dendritic loss. This system provides new insights into the mechanisms responsible for prion neurotoxicity, and it provides a platform for characterizing different pathogenic forms of PrPSc and testing potential therapeutic agents.

  12. [Lyme disease--clinical manifestations and treatment].

    Science.gov (United States)

    Stock, Ingo

    2016-05-01

    Lyme disease (Lyme borreliosis) is a systemic infectious disease that can present in a variety of clinical manifestations. The disease is caused by a group of spirochaetes--Borrelia burgdorferi sensu lato or Lyme borrelia--that are transmitted to humans by the bite of Ixodes ticks. Lyme disease is the most common arthropode-borne infectious disease in many European countries including Germany. Early localized infection is typically manifested by an erythema migrans skin lesion, in rarer cases as a borrelial lymphocytoma. The most common early disseminated manifestation is (early) neuroborreliosis. In adults, neuroborreliosis appears typically as meningoradiculoneuritis. Neuroborreliosis in children, however, is typically manifested by meningitis. In addition, multiple erythema migrans lesions and Lyme carditis occur relatively frequently. The most common manifestation oflate Lyme disease is Lyme arthritis. Early manifestations (and usually also late manifestations) of Lyme disease can be treated successfully by application of suitable antibacterial agents. For the treatment of Lyme disease, doxycycline, certain penicillins such as amoxicillin and some cephalosporins (ceftriaxone, cefotaxime, cefuroxime axetil) are recommended in current guidelines. A major challenge is the treatment of chronic, non-specific disorders, i. e., posttreatment Lyme disease syndrome and "chronic Lyme disease". Prevention of Lyme disease is mainly accomplished by protecting against tick bites. Prophylactic administration of doxycycline after tick bites is generally not recommended in Germany. There is no vaccine available for human beings.

  13. [Lyme disease--clinical manifestations and treatment].

    Science.gov (United States)

    Stock, Ingo

    2016-05-01

    Lyme disease (Lyme borreliosis) is a systemic infectious disease that can present in a variety of clinical manifestations. The disease is caused by a group of spirochaetes--Borrelia burgdorferi sensu lato or Lyme borrelia--that are transmitted to humans by the bite of Ixodes ticks. Lyme disease is the most common arthropode-borne infectious disease in many European countries including Germany. Early localized infection is typically manifested by an erythema migrans skin lesion, in rarer cases as a borrelial lymphocytoma. The most common early disseminated manifestation is (early) neuroborreliosis. In adults, neuroborreliosis appears typically as meningoradiculoneuritis. Neuroborreliosis in children, however, is typically manifested by meningitis. In addition, multiple erythema migrans lesions and Lyme carditis occur relatively frequently. The most common manifestation oflate Lyme disease is Lyme arthritis. Early manifestations (and usually also late manifestations) of Lyme disease can be treated successfully by application of suitable antibacterial agents. For the treatment of Lyme disease, doxycycline, certain penicillins such as amoxicillin and some cephalosporins (ceftriaxone, cefotaxime, cefuroxime axetil) are recommended in current guidelines. A major challenge is the treatment of chronic, non-specific disorders, i. e., posttreatment Lyme disease syndrome and "chronic Lyme disease". Prevention of Lyme disease is mainly accomplished by protecting against tick bites. Prophylactic administration of doxycycline after tick bites is generally not recommended in Germany. There is no vaccine available for human beings. PMID:27348896

  14. Clinical Manifestations of Type 1 Gaucher Disease

    Directory of Open Access Journals (Sweden)

    Shadab SALEHPOUR

    2012-12-01

    Full Text Available  How to Cite this Article: Salehpour Sh. Clinical Manifestations of Type 1 Gaucher Disease. Iran J Child Neurol Autumn 2012; 6:4 (suppl. 1:13-14.pls see PDF.References 1. Beutler E, Grabowski GA. Gaucher disease. In: Metabolic and molecular bases of inherited disease, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds, McGraw-Hill, New York 2001: 3635. 2. Cox TM, Schofield JP.   Gaucher’s disease: clinical features  and   natural   history.   Baillieres   Clin Haematol. 1997 Dec;10(4:657-89.   

  15. Protease-Sensitive Synthetic Prions

    OpenAIRE

    Colby, David W; Rachel Wain; Baskakov, Ilia V.; Giuseppe Legname; Palmer, Christina G.; Nguyen, Hoang-Oanh B.; Azucena Lemus; Cohen, Fred E.; Stephen J DeArmond; Prusiner, Stanley B.

    2010-01-01

    Prions arise when the cellular prion protein (PrP(C)) undergoes a self-propagating conformational change; the resulting infectious conformer is designated PrP(Sc). Frequently, PrP(Sc) is protease-resistant but protease-sensitive (s) prions have been isolated in humans and other animals. We report here that protease-sensitive, synthetic prions were generated in vitro during polymerization of recombinant (rec) PrP into amyloid fibers. In 22 independent experiments, recPrP amyloid preparations, ...

  16. A cationic tetrapyrrole inhibits toxic activities of the cellular prion protein.

    Science.gov (United States)

    Massignan, Tania; Cimini, Sara; Stincardini, Claudia; Cerovic, Milica; Vanni, Ilaria; Elezgarai, Saioa R; Moreno, Jorge; Stravalaci, Matteo; Negro, Alessandro; Sangiovanni, Valeria; Restelli, Elena; Riccardi, Geraldina; Gobbi, Marco; Castilla, Joaquín; Borsello, Tiziana; Nonno, Romolo; Biasini, Emiliano

    2016-01-01

    Prion diseases are rare neurodegenerative conditions associated with the conformational conversion of the cellular prion protein (PrP(C)) into PrP(Sc), a self-replicating isoform (prion) that accumulates in the central nervous system of affected individuals. The structure of PrP(Sc) is poorly defined, and likely to be heterogeneous, as suggested by the existence of different prion strains. The latter represents a relevant problem for therapy in prion diseases, as some potent anti-prion compounds have shown strain-specificity. Designing therapeutics that target PrP(C) may provide an opportunity to overcome these problems. PrP(C) ligands may theoretically inhibit the replication of multiple prion strains, by acting on the common substrate of any prion replication reaction. Here, we characterized the properties of a cationic tetrapyrrole [Fe(III)-TMPyP], which was previously shown to bind PrP(C), and inhibit the replication of a mouse prion strain. We report that the compound is active against multiple prion strains in vitro and in cells. Interestingly, we also find that Fe(III)-TMPyP inhibits several PrP(C)-related toxic activities, including the channel-forming ability of a PrP mutant, and the PrP(C)-dependent synaptotoxicity of amyloid-β (Aβ) oligomers, which are associated with Alzheimer's Disease. These results demonstrate that molecules binding to PrP(C) may produce a dual effect of blocking prion replication and inhibiting PrP(C)-mediated toxicity. PMID:26976106

  17. A bovine cell line that can be infected by natural sheep scrapie prions.

    Directory of Open Access Journals (Sweden)

    Anja M Oelschlegel

    Full Text Available Cell culture systems represent a crucial part in basic prion research; yet, cell lines that are susceptible to prions, especially to field isolated prions that were not adapted to rodents, are very rare. The purpose of this study was to identify and characterize a cell line that was susceptible to ruminant-derived prions and to establish a stable prion infection within it. Based on species and tissue of origin as well as PrP expression rate, we pre-selected a total of 33 cell lines that were then challenged with natural and with mouse propagated BSE or scrapie inocula. Here, we report the successful infection of a non-transgenic bovine cell line, a sub-line of the bovine kidney cell line MDBK, with natural sheep scrapie prions. This cell line retained the scrapie infection for more than 200 passages. Selective cloning resulted in cell populations with increased accumulation of PrPres, although this treatment was not mandatory for retaining the infection. The infection remained stable, even under suboptimal culture conditions. The resulting infectivity of the cells was confirmed by mouse bioassay (Tgbov mice, Tgshp mice. We believe that PES cells used together with other prion permissive cell lines will prove a valuable tool for ongoing efforts to understand and defeat prions and prion diseases.

  18. A bovine cell line that can be infected by natural sheep scrapie prions.

    Science.gov (United States)

    Oelschlegel, Anja M; Geissen, Markus; Lenk, Matthias; Riebe, Roland; Angermann, Marlies; Schatzl, Herman; Schaetzl, Hermann; Groschup, Martin H

    2015-01-01

    Cell culture systems represent a crucial part in basic prion research; yet, cell lines that are susceptible to prions, especially to field isolated prions that were not adapted to rodents, are very rare. The purpose of this study was to identify and characterize a cell line that was susceptible to ruminant-derived prions and to establish a stable prion infection within it. Based on species and tissue of origin as well as PrP expression rate, we pre-selected a total of 33 cell lines that were then challenged with natural and with mouse propagated BSE or scrapie inocula. Here, we report the successful infection of a non-transgenic bovine cell line, a sub-line of the bovine kidney cell line MDBK, with natural sheep scrapie prions. This cell line retained the scrapie infection for more than 200 passages. Selective cloning resulted in cell populations with increased accumulation of PrPres, although this treatment was not mandatory for retaining the infection. The infection remained stable, even under suboptimal culture conditions. The resulting infectivity of the cells was confirmed by mouse bioassay (Tgbov mice, Tgshp mice). We believe that PES cells used together with other prion permissive cell lines will prove a valuable tool for ongoing efforts to understand and defeat prions and prion diseases.

  19. Sialylation of prion protein controls the rate of prion amplification, the cross-species barrier, the ratio of PrPSc glycoform and prion infectivity.

    Directory of Open Access Journals (Sweden)

    Elizaveta Katorcha

    2014-09-01

    Full Text Available The central event underlying prion diseases involves conformational change of the cellular form of the prion protein (PrP(C into the disease-associated, transmissible form (PrP(Sc. Pr(PC is a sialoglycoprotein that contains two conserved N-glycosylation sites. Among the key parameters that control prion replication identified over the years are amino acid sequence of host PrP(C and the strain-specific structure of PrPSc. The current work highlights the previously unappreciated role of sialylation of PrP(C glycans in prion pathogenesis, including its role in controlling prion replication rate, infectivity, cross-species barrier and PrP(Sc glycoform ratio. The current study demonstrates that undersialylated PrP(C is selected during prion amplification in Protein Misfolding Cyclic Amplification (PMCAb at the expense of oversialylated PrP(C. As a result, PMCAb-derived PrP(Sc was less sialylated than brain-derived PrP(Sc. A decrease in PrPSc sialylation correlated with a drop in infectivity of PMCAb-derived material. Nevertheless, enzymatic de-sialylation of PrP(C using sialidase was found to increase the rate of PrP(Sc amplification in PMCAb from 10- to 10,000-fold in a strain-dependent manner. Moreover, de-sialylation of PrP(C reduced or eliminated a species barrier of for prion amplification in PMCAb. These results suggest that the negative charge of sialic acid controls the energy barrier of homologous and heterologous prion replication. Surprisingly, the sialylation status of PrP(C was also found to control PrP(Sc glycoform ratio. A decrease in Pr(PC sialylation levels resulted in a higher percentage of the diglycosylated glycoform in PrP(Sc. 2D analysis of charge distribution revealed that the sialylation status of brain-derived PrP(C differed from that of spleen-derived PrP(C. Knocking out lysosomal sialidase Neu1 did not change the sialylation status of brain-derived PrP(C, suggesting that Neu1 is not responsible for desialylation of Pr

  20. Prion pathogenesis is unaltered following down-regulation of SIGN-R1.

    Science.gov (United States)

    Bradford, Barry M; Brown, Karen L; Mabbott, Neil A

    2016-10-01

    Prion diseases are infectious neurodegenerative disorders characterised by accumulations of abnormal prion glycoprotein in affected tissues. Following peripheral exposure, many prion strains replicate upon follicular dendritic cells (FDC) in lymphoid tissues before infecting the brain. An intact splenic marginal zone is important for the efficient delivery of prions to FDC. The marginal zone contains a ring of specific intercellular adhesion molecule-3-grabbing non-integrin related 1 (SIGN-R1)-expressing macrophages. This lectin binds dextran and capsular pneumococcal polysaccharides, and also enhances the clearance of apoptotic cells via interactions with complement components. Since prions are acquired as complement-opsonized complexes we determined the role of SIGN-R1 in disease pathogenesis. We show that transient down-regulation of SIGN-R1 prior to intravenous prion exposure had no effect on the early accumulation of prions upon splenic FDC or their subsequent spread to the brain. Thus, SIGN-R1 expression by marginal zone macrophages is not rate-limiting for peripheral prion disease pathogenesis.

  1. Structural determinants of phenotypic diversity and replication rate of human prions.

    Directory of Open Access Journals (Sweden)

    Jiri G Safar

    2015-04-01

    Full Text Available The infectious pathogen responsible for prion diseases is the misfolded, aggregated form of the prion protein, PrPSc. In contrast to recent progress in studies of laboratory rodent-adapted prions, current understanding of the molecular basis of human prion diseases and, especially, their vast phenotypic diversity is very limited. Here, we have purified proteinase resistant PrPSc aggregates from two major phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD, determined their conformational stability and replication tempo in vitro, as well as characterized structural organization using recently emerged approaches based on hydrogen/deuterium (H/D exchange coupled with mass spectrometry. Our data clearly demonstrate that these phenotypically distant prions differ in a major way with regard to their structural organization, both at the level of the polypeptide backbone (as indicated by backbone amide H/D exchange data as well as the quaternary packing arrangements (as indicated by H/D exchange kinetics for histidine side chains. Furthermore, these data indicate that, in contrast to previous observations on yeast and some murine prion strains, the replication rate of sCJD prions is primarily determined not by conformational stability but by specific structural features that control the growth rate of prion protein aggregates.

  2. Prion Infection of Mouse Brain Reveals Multiple New Upregulated Genes Involved in Neuroinflammation or Signal Transduction

    OpenAIRE

    Carroll, James A.; Striebel, James F.; Race, Brent; Phillips, Katie; Chesebro, Bruce

    2014-01-01

    Gliosis is often a preclinical pathological finding in neurodegenerative diseases, including prion diseases, but the mechanisms facilitating gliosis and neuronal damage in these diseases are not understood. To expand our knowledge of the neuroinflammatory response in prion diseases, we assessed the expression of key genes and proteins involved in the inflammatory response and signal transduction in mouse brain at various times after scrapie infection. In brains of scrapie-infected mice at pre...

  3. Concentration-dependent Cu(II) binding to prion protein

    Science.gov (United States)

    Hodak, Miroslav; Lu, Wenchang; Bernholc, Jerry

    2008-03-01

    The prion protein plays a causative role in several neurodegenerative diseases, including mad cow disease in cattle and Creutzfeldt-Jakob disease in humans. The normal function of the prion protein is unknown, but it has been linked to its ability to bind copper ions. Experimental evidence suggests that copper can be bound in three distinct modes depending on its concentration, but only one of those binding modes has been fully characterized experimentally. Using a newly developed hybrid DFT/DFT method [1], which combines Kohn-Sham DFT with orbital-free DFT, we have examined all the binding modes and obtained their detailed binding geometries and copper ion binding energies. Our results also provide explanation for experiments, which have found that when the copper concentration increases the copper binding mode changes, surprisingly, from a stronger to a weaker one. Overall, our results indicate that prion protein can function as a copper buffer. 1. Hodak, Lu, Bernholc, JCP, in press.

  4. Red-backed vole brain promotes highly efficient in vitro amplification of abnormal prion protein from macaque and human brains infected with variant Creutzfeldt-Jakob disease agent.

    Science.gov (United States)

    Nemecek, Julie; Nag, Nabanita; Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.; Asher, David M.; Gregori, Luisa

    2013-01-01

    Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10-12 of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in v

  5. Red-backed vole brain promotes highly efficient in vitro amplification of abnormal prion protein from macaque and human brains infected with variant Creutzfeldt-Jakob disease agent.

    Directory of Open Access Journals (Sweden)

    Julie Nemecek

    Full Text Available Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA to amplify abnormal prion protein (PrP(TSE from highly diluted variant Creutzfeldt-Jakob disease (vCJD-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrP(TSE in tissues and blood. Macaque vCJD PrP(TSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA. Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV, a close relative of the bank vole, seeded with macaque vCJD PrP(TSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N. We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrP(TSE. Meadow vole brain (170N/N PrP genotype was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrP(TSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrP(TSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrP(TSE was more permissive than human PrP(TSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrP(TSE from brains of humans and macaques with vCJD. PrP(TSE signals were reproducibly detected by Western blot in dilutions through 10⁻¹² of vCJD-infected 10% brain homogenates. This is the first report showing PrP(TSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect Pr

  6. Immunopurification of pathological prion protein aggregates.

    Directory of Open Access Journals (Sweden)

    Emiliano Biasini

    Full Text Available BACKGROUND: Prion diseases are fatal neurodegenerative disorders that can arise sporadically, be genetically inherited or acquired through infection. The key event in these diseases is misfolding of the cellular prion protein (PrP(C into a pathogenic isoform that is rich in beta-sheet structure. This conformational change may result in the formation of PrP(Sc, the prion isoform of PrP, which propagates itself by imprinting its aberrant conformation onto PrP(C molecules. A great deal of effort has been devoted to developing protocols for purifying PrP(Sc for structural studies, and testing its biological properties. Most procedures rely on protease digestion, allowing efficient purification of PrP27-30, the protease-resistant core of PrP(Sc. However, protease treatment cannot be used to isolate abnormal forms of PrP lacking conventional protease resistance, such as those found in several genetic and atypical sporadic cases. PRINCIPAL FINDINGS: We developed a method for purifying pathological PrP molecules based on sequential centrifugation and immunoprecipitation with a monoclonal antibody selective for aggregated PrP. With this procedure we purified full-length PrP(Sc and mutant PrP aggregates at electrophoretic homogeneity. PrP(Sc purified from prion-infected mice was able to seed misfolding of PrP(C in a protein misfolding cyclic amplification reaction, and mutant PrP aggregates from transgenic mice were toxic to cultured neurons. SIGNIFICANCE: The immunopurification protocol described here isolates biologically active forms of aggregated PrP. These preparations may be useful for investigating the structural and chemico-physical properties of infectious and neurotoxic PrP aggregates.

  7. Smart Technology in Lung Disease Clinical Trials.

    Science.gov (United States)

    Geller, Nancy L; Kim, Dong-Yun; Tian, Xin

    2016-01-01

    This article describes the use of smart technology by investigators and patients to facilitate lung disease clinical trials and make them less costly and more efficient. By "smart technology" we include various electronic media, such as computer databases, the Internet, and mobile devices. We first describe the use of electronic health records for identifying potential subjects and then discuss electronic informed consent. We give several examples of using the Internet and mobile technology in clinical trials. Interventions have been delivered via the World Wide Web or via mobile devices, and both have been used to collect outcome data. We discuss examples of new electronic devices that recently have been introduced to collect health data. While use of smart technology in clinical trials is an exciting development, comparison with similar interventions applied in a conventional manner is still in its infancy. We discuss advantages and disadvantages of using this omnipresent, powerful tool in clinical trials, as well as directions for future research.

  8. Smart Technology in Lung Disease Clinical Trials.

    Science.gov (United States)

    Geller, Nancy L; Kim, Dong-Yun; Tian, Xin

    2016-01-01

    This article describes the use of smart technology by investigators and patients to facilitate lung disease clinical trials and make them less costly and more efficient. By "smart technology" we include various electronic media, such as computer databases, the Internet, and mobile devices. We first describe the use of electronic health records for identifying potential subjects and then discuss electronic informed consent. We give several examples of using the Internet and mobile technology in clinical trials. Interventions have been delivered via the World Wide Web or via mobile devices, and both have been used to collect outcome data. We discuss examples of new electronic devices that recently have been introduced to collect health data. While use of smart technology in clinical trials is an exciting development, comparison with similar interventions applied in a conventional manner is still in its infancy. We discuss advantages and disadvantages of using this omnipresent, powerful tool in clinical trials, as well as directions for future research. PMID:26135330

  9. Infectious prions accumulate to high levels in non proliferative C2C12 myotubes.

    Directory of Open Access Journals (Sweden)

    Allen Herbst

    Full Text Available Prion diseases are driven by the strain-specific, template-dependent transconformation of the normal cellular prion protein (PrP(C into a disease specific isoform PrP(Sc. Cell culture models of prion infection generally use replicating cells resulting in lower levels of prion accumulation compared to animals. Using non-replicating cells allows the accumulation of higher levels of PrP(Sc and, thus, greater amounts of infectivity. Here, we infect non-proliferating muscle fiber myotube cultures prepared from differentiated myoblasts. We demonstrate that prion-infected myotubes generate substantial amounts of PrP(Sc and that the level of infectivity produced in these post-mitotic cells, 10(5.5 L.D.50/mg of total protein, approaches that observed in vivo. Exposure of the myotubes to different mouse-adapted agents demonstrates strain-specific replication of infectious agents. Mouse-derived myotubes could not be infected with hamster prions suggesting that the species barrier effect is intact. We suggest that non-proliferating myotubes will be a valuable model system for generating infectious prions and for screening compounds for anti-prion activity.

  10. Interfaces between dendritic cells, other immune cells, and nerve fibres in mouse Peyer's patches: potential sites for neuroinvasion in prion diseases.

    Science.gov (United States)

    Defaweux, Valérie; Dorban, Gauthier; Demonceau, Caroline; Piret, Joëlle; Jolois, Olivier; Thellin, Olivier; Thielen, Caroline; Heinen, Ernst; Antoine, Nadine

    2005-01-01

    In this study, we examined where immune cells and nerve fibres are located in mouse Peyer's patches, with a view to identifying potential sites for neuroinvasion by prions. Special attention was paid to dendritic cells, viewed as candidate transporters of infectious prion. Double immunofluorescence labellings with anti-CD11c antibody and marker for other immune cells (B cells, T cells, follicular dendritic cells) were carried out and analysed by confocal microscopy on Peyer's patch cryosections. To reveal the extensive ganglionated networks of the myenteric and submucosal plexi and the sparse meshworks of nerve strands, we used antibodies directed against different neurofilament subunits or against glial fibrillary acidic protein. In the suprafollicular dome, dendritic cells connect, via their cytoplasmic extensions, enterocytes with M cells of the follicle-associated epithelium. They are also close to B and T cells. Nerve fibres are detected in the suprafollicular dome, notably in contact with dendritic cells. Similar connections between dendritic cells, T cells, and nerve fibres are seen in the interfollicular region. Germinal centres are not innervated; inside them dendritic cells establish contacts with follicular dendritic cells and with B cells. After immunolabelling of normal prion protein, dendritic cells of the suprafollicular dome are intensely positive labelled. PMID:15816033

  11. Prion-Specific Antibodies Produced in Wild-Type Mice

    DEFF Research Database (Denmark)

    Heegaard, Peter M. H.; Bergström, Ann-Louise; Andersen, Heidi Gertz;

    2015-01-01

    method for production of mouse monoclonal antibodies (MAbs) against peptides representing two sites of interest in the bovine prion protein (boPrP), the causative agent of bovine spongiform encephalopathy ("mad cow disease") and new variant Creutzfeldt-Jakob's disease (CJD) in humans, as well...... as a thorough characterization of their reactivity with a range of normal and pathogenic (misfolded) prion proteins. It is demonstrated that immunization of wild-type mice with ovalbumin-conjugated peptides formulated with Freund's adjuvant induces a good immune response, including high levels of specific anti...

  12. Dissection and design of yeast prions.

    OpenAIRE

    Osherovich, Lev Z; Cox, Brian S; Mick F Tuite; Weissman, Jonathan S

    2004-01-01

    Many proteins can misfold into beta-sheet-rich, self-seeding polymers (amyloids). Prions are exceptional among such aggregates in that they are also infectious. In fungi, prions are not pathogenic but rather act as epigenetic regulators of cell physiology, providing a powerful model for studying the mechanism of prion replication. We used prion-forming domains from two budding yeast proteins (Sup35p and New1p) to examine the requirements for prion formation and inheritance. In both proteins, ...

  13. B Cell-Specific S1PR1-Deficiency Blocks Prion Dissemination Between Secondary Lymphoid Organs1

    OpenAIRE

    Mok, Simon W. F.; Proia, Richard L.; Brinkmann, Volker; Mabbott, Neil A.

    2012-01-01

    Many prion diseases are peripherally acquired (eg. orally or via lesions to skin or mucous membranes). After peripheral exposure prions replicate first upon follicular dendritic cells (FDC) in the draining lymphoid tissue before infecting the brain. However, after replication upon FDC within the draining lymphoid tissue, prions are subsequently propagated to most non-draining secondary lymphoid organs (SLO) including the spleen by a previously underdetermined mechanism. The germinal centres i...

  14. Humic substances interfere with detection of pathogenic prion protein

    Science.gov (United States)

    Smith, Christen B.; Booth, Clarissa J.; Wadzinski, Tyler J.; Legname, Giuseppe; Chappell, Rick; Johnson, Christopher J.; Pedersen, Joel A.

    2014-01-01

    Studies examining the persistence of prions (the etiological agent of transmissible spongiform encephalopathies) in soil require accurate quantification of pathogenic prion protein (PrPTSE) extracted from or in the presence of soil particles. Here, we demonstrate that natural organic matter (NOM) in soil impacts PrPTSE detection by immunoblotting. Methods commonly used to extract PrPTSE from soils release substantial amounts of NOM, and NOM inhibited PrPTSE immunoblot signal. The degree of immunoblot interference increased with increasing NOM concentration and decreasing NOM polarity. Humic substances affected immunoblot detection of prion protein from both deer and hamsters. We also establish that after interaction with humic acid, PrPTSE remains infectious to hamsters inoculated intracerebrally, and humic acid appeared to slow disease progression. These results provide evidence for interactions between PrPTSE and humic substances that influence both accurate measurement of PrPTSE in soil and disease transmission.

  15. Disease: H00061 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H00061 Prion diseases; Creutzfeldt-Jacob disease (CJD); Gerstmann-Straussler diseas...e (GSD); Gerstmann-Straussler-Scheinker disease (GSSD); Fatal familial insomnia (FFI) Prion diseases, also t...ermed transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative diseases that... affect humans and a number of other animal species. The etiology of these diseases...vely folded protein, PrPC. Neurodegenerative disease hsa05020 Prion diseases PRNP (mutation) [HSA:5621] [KO:

  16. Evidence that bank vole PrP is a universal acceptor for prions.

    Directory of Open Access Journals (Sweden)

    Joel C Watts

    2014-04-01

    Full Text Available Bank voles are uniquely susceptible to a wide range of prion strains isolated from many different species. To determine if this enhanced susceptibility to interspecies prion transmission is encoded within the sequence of the bank vole prion protein (BVPrP, we inoculated Tg(M109 and Tg(I109 mice, which express BVPrP containing either methionine or isoleucine at polymorphic codon 109, with 16 prion isolates from 8 different species: humans, cattle, elk, sheep, guinea pigs, hamsters, mice, and meadow voles. Efficient disease transmission was observed in both Tg(M109 and Tg(I109 mice. For instance, inoculation of the most common human prion strain, sporadic Creutzfeldt-Jakob disease (sCJD subtype MM1, into Tg(M109 mice gave incubation periods of ∼200 days that were shortened slightly on second passage. Chronic wasting disease prions exhibited an incubation time of ∼250 days, which shortened to ∼150 days upon second passage in Tg(M109 mice. Unexpectedly, bovine spongiform encephalopathy and variant CJD prions caused rapid neurological dysfunction in Tg(M109 mice upon second passage, with incubation periods of 64 and 40 days, respectively. Despite the rapid incubation periods, other strain-specified properties of many prion isolates--including the size of proteinase K-resistant PrPSc, the pattern of cerebral PrPSc deposition, and the conformational stability--were remarkably conserved upon serial passage in Tg(M109 mice. Our results demonstrate that expression of BVPrP is sufficient to engender enhanced susceptibility to a diverse range of prion isolates, suggesting that BVPrP may be a universal acceptor for prions.

  17. Analysis of factors that modulate the toxicity of the yeast prion protein Rnq1

    OpenAIRE

    Li, Zhiyuan

    2016-01-01

    Prions are infectious proteins that form transmissible, self-propagating amyloids that convert protein from its normal state into the prion state. The accumulation of amyloid is the causative agent of several neurodegenerative diseases, for instance, Huntington’s disease, which is caused by a polyglutamine expansion in the huntingtin (Htt) protein. In this study, a yeast-based Huntington’s disease model was created to investigate the mechanism of amyloid toxicity and how nuclear genes modulat...

  18. Transmission of scrapie prions to primate after an extended silent incubation period

    OpenAIRE

    Emmanuel E Comoy; Mikol, Jacqueline; Luccantoni-Freire, Sophie; Correia, Evelyne; Lescoutra-Etchegaray, Nathalie; Durand, Valérie; Dehen, Capucine; Andreoletti, Olivier; Casalone, Cristina; Richt, Juergen A.; Greenlee, Justin J.; Baron, Thierry; Benestad, Sylvie L.; Brown, Paul; Deslys, Jean-Philippe

    2015-01-01

    Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans and having guided protective measures for animal and human health against animal prion diseases. Recently, partial transmissions to humanized mice showed that the zoonotic potential of scrapie might be similar to c-BSE. We here report the direct transmission of a natural classical scrapie isolate to cynomolgus macaque, a highly ...

  19. Clinic Practical Guides for Cerebrovascular Diseases

    OpenAIRE

    Miguel Angel Buergo Zuaznábar; Otman Fernández Concepción; Jesús Pérez Nellar; Gloria Lara Fernández; Carlos Maya Entenza; Alejandro Pando Cabrera

    2007-01-01

    The clinic practical guides for cerebrovascular diseases are presented. They include different aspects as its concept, classification, and epidemiological data in Cuba as well as worldwide. They also offer its diagnosis, classification, complications and treatment. The frequency of assessment of its application including the tools to measure the quality of life in patients with cerebrovascular accident and the way to proceed with them are shown

  20. Manipulating the Prion Protein Gene Sequence and Expression Levels with CRISPR/Cas9.

    Science.gov (United States)

    Kaczmarczyk, Lech; Mende, Ylva; Zevnik, Branko; Jackson, Walker S

    2016-01-01

    The mammalian prion protein (PrP, encoded by Prnp) is most infamous for its central role in prion diseases, invariably fatal neurodegenerative diseases affecting humans, food animals, and animals in the wild. However, PrP is also hypothesized to be an important receptor for toxic protein conformers in Alzheimer's disease, and is associated with other clinically relevant processes such as cancer and stroke. Thus, key insights into important clinical areas, as well as into understanding PrP functions in normal physiology, can be obtained from studying transgenic mouse models and cell culture systems. However, the Prnp locus is difficult to manipulate by homologous recombination, making modifications of the endogenous locus rarely attempted. Fortunately in recent years genome engineering technologies, like TALENs or CRISPR/Cas9 (CC9), have brought exceptional new possibilities for manipulating Prnp. Herein, we present our observations made during systematic experiments with the CC9 system targeting the endogenous mouse Prnp locus, to either modify sequences or to boost PrP expression using CC9-based synergistic activation mediators (SAMs). It is our hope that this information will aid and encourage researchers to implement gene-targeting techniques into their research program. PMID:27128441