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The Veterinary Quarterly Sep 2011Transmissible spongiform encephalopathies (TSEs) or prion diseases are unique disorders that are not caused by infectious micro-organisms (bacteria or fungi), viruses or... (Review)
Review
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 affecting both human and animals. Prion diseases cause sponge-like degeneration of neuronal tissue and include (among others) Creutzfeldt-Jacob disease in humans, bovine spongiform encephalopathy (BSE) in cattle and scrapie in sheep. TSEs are characterized by the formation and accumulation of transmissible (infectious) disease-associated protease-resistant prion protein (PrP(Sc)), mainly in tissues of the central nervous system. The exact molecular processes behind the conversion of PrP(C) into PrP(Sc) are not clearly understood. Correlations between prion protein polymorphisms and disease have been found, however in what way these polymorphisms influence the conversion processes remains an enigma; is stabilization or destabilization of the prion protein the basis for a higher conversion propensity? Apart from the disease-associated polymorphisms of the prion protein, the molecular processes underlying conversion are not understood. There are some notions as to which regions of the prion protein are involved in refolding of PrP(C) into PrP(Sc) and where the most drastic structural changes take place. Direct interactions between PrP(C) molecules and/or PrP(Sc) are likely at the basis of conversion, however which specific amino acid domains are involved and to what extent these domains contribute to conversion resistance/sensitivity of the prion protein or the species barrier is still unknown.
Topics: Animals; Cattle; Creutzfeldt-Jakob Syndrome; Humans; Polymorphism, Genetic; Prion Diseases; Prions; Scrapie; Sheep
PubMed: 22029882
DOI: 10.1080/01652176.2011.604976 -
Clinics in Laboratory Medicine Mar 2003The main goals of this article have been to summarize our current understanding of the biology of PrP, the propagation of prions, and the etiology and pathogenesis of... (Review)
Review
The main goals of this article have been to summarize our current understanding of the biology of PrP, the propagation of prions, and the etiology and pathogenesis of each form of prion disease (familial, sporadic, and infectious); and to review current rational pharmacologic strategies for treatment of prion diseases. Each of these subjects is presented primarily from the perspective of investigations performed by the prion disease research laboratories at the University of California in San Francisco and by its many collaborators in the United States and abroad. This review focuses on key results from the hundreds of transgenic mouse lines expressing different PrP constructs that have been used to determine the roles played by different PrPSc and PrPC domains in prion propagation and the prion disease phenotype.
Topics: Animals; Humans; Mice; Mice, Transgenic; Models, Molecular; Prion Diseases; Prions
PubMed: 12733423
DOI: 10.1016/s0272-2712(02)00041-0 -
Expert Opinion on Drug Discovery Oct 2013Prion diseases, also known as transmissible spongiform encephalopathies, are a group of neurodegenerative diseases that are invariably incurable. In fact, intense... (Review)
Review
INTRODUCTION
Prion diseases, also known as transmissible spongiform encephalopathies, are a group of neurodegenerative diseases that are invariably incurable. In fact, intense laboratory and clinical research have failed to discover effective treatments, to date, which delay the onset or progression of any neurodegenerative conditions, including those caused by infectious prions. It has become clear that profound changes in the brains of patients are evident long before clinical signs and it is at this stage that the disease is reversible and presents 'druggable' targets. However, research is beginning to uncover the molecular underpinnings involved in the early stages of disease pathogenesis. Targeting key genes and pathways using short non-coding RNA is a new avenue of exploratory research for the treatment of prion disease that holds much promise for the future.
AREAS COVERED
This article reviews the novel approach of using RNA-based drugs as a therapeutic opportunity for prion disease. Furthermore, it discusses the challenges that currently exist in the development of these therapies and highlights the future opportunities in this area.
EXPERT OPINION
Numerous challenges exist before this therapeutic option can be translated into effective treatments. First, the crucial genes and pathways targeted must be identified from the multitude of temporally and spatially altered genetic processes that occur during the disease. Second, patients must be before irreversible neuronal degeneration, that accompanies prion replication, has progressed. Finally, these small RNAs must be delivered to the affected region of the brain over long periods of time and without significant side effects.
Topics: Animals; Drug Delivery Systems; Humans; Molecular Targeted Therapy; Prion Diseases; Prions; Protein Refolding; RNA Interference; RNA, Small Interfering; Transfection
PubMed: 23848240
DOI: 10.1517/17460441.2013.818976 -
Rinsho Shinkeigaku = Clinical Neurology Nov 2008There have been identified 1051 cases of prion dsease in Japan since 1999 by the surveillance committee, of which idiopathic prion disease held 77.8%, hereditary 15.9%... (Review)
Review
There have been identified 1051 cases of prion dsease in Japan since 1999 by the surveillance committee, of which idiopathic prion disease held 77.8%, hereditary 15.9% and infectious 6.6%. Idiopathic prion disease is sporadic Creutzfeldt-Jakob disease (sCJD) and most sCJD cases were classified into MM1 presenting with classical clinical features. MM2, MV2, VV1 and VV2 sCJD cases were rare and showed atypical features including prolonged course, lack of myoclonus and absence of PSD. In such occasions, high signal intensities on DW-MRI as well as increased 14-3-3 and tau proteins in CSF were very helpful. MM2 tharamic sCJD may lack all these laboratory findings but reduction of tharamic CBF in SPECT or PET would support the diagnosis. Hereditary prion disease are classified into 3 major phenotypes such as familial CJD, Gerstmann-Straeussler-Scheinker disease (GSS) mainly showing spinocerebellar ataxia, and fatal familial insomunia. While there have been known many mutations of prion protein gene, only V180I (fCJD), E200K (fCJD), M232R (fCJD) and P102L (GSS) mutations were common. Because most cases did not have family history, genetic test is mandatory in all the cases of prion disease including seemingly "sporadic" CJD. All the cases but 1 case of variant CJD were dura-grafted CJD in infectious prion disease.
Topics: 14-3-3 Proteins; Animals; Biomarkers; Humans; Japan; Magnetic Resonance Imaging; Mutation; Prion Diseases; Prions; tau Proteins
PubMed: 19198101
DOI: 10.5692/clinicalneurol.48.861 -
Drugs of Today (Barcelona, Spain : 1998) Jan 2002Apoptotic neuronal cell death is a hallmark of prion diseases. The apoptotic process in neuronal cells is thought to be caused by the scrapie prion protein, PrPSc, and... (Review)
Review
Apoptotic neuronal cell death is a hallmark of prion diseases. The apoptotic process in neuronal cells is thought to be caused by the scrapie prion protein, PrPSc, and can be experimentally induced by its peptide fragment, PrP106-126. This process is a target for potential drugs to combat prion disease or to ameliorate its symptoms. Flupirtine (Katadolon), a pyridine derivative that is in clinical use as a nonopioid analgesic, has a potent cytoprotective effect, at concentrations above 1 microg/mL, on neuronal cells treated with PrP(Sc) or PrP106-126. This drug acts as an N-methyl-D-aspartate (NMDA) antagonist, but does not bind to NMDA receptors. Flupirtine normalizes the level of intracellular glutathione and increases the expression of the antiapoptotic Bcl-2 protein in neuronal cells exposed to prion protein. In view of its favorable pharmacokinetic profile, flupirtine is the first drug to be considered as a potential treatment for Creutzfeldt-Jakob disease, the human form of prion diseases. Clinical trials are underway.
Topics: Aminopyridines; Animals; Calcium; Genes, bcl-2; Glutathione; Humans; Neuroprotective Agents; Prion Diseases
PubMed: 12532184
DOI: 10.1358/dot.2002.38.1.660505 -
The Journal of Biological Chemistry Mar 2018Prion diseases are a group of fatal neurodegenerative diseases associated with a protein-based infectious agent, termed prion. Compelling evidence suggests that natural...
Prion diseases are a group of fatal neurodegenerative diseases associated with a protein-based infectious agent, termed prion. Compelling evidence suggests that natural transmission of prion diseases is mediated by environmental contamination with infectious prions. We hypothesized that several natural and man-made materials, commonly found in the environments of wild and captive animals, can bind prions and may act as vectors for disease transmission. To test our hypothesis, we exposed surfaces composed of various common environmental materials ( wood, rocks, plastic, glass, cement, stainless steel, aluminum, and brass) to hamster-adapted 263K scrapie prions and studied their attachment and retention of infectivity and Our results indicated that these surfaces, with the sole exception of brass, efficiently bind, retain, and release prions. Prion replication was studied using the protein misfolding cyclic amplification technology, and infectivity of surface-bound prions was analyzed by intracerebrally challenging hamsters with contaminated implants. Our results revealed that virtually all prion-contaminated materials transmitted the disease at high rates. To investigate a more natural form of exposure to environmental contamination, we simply housed animals with large contaminated spheres made of the different materials under study. Strikingly, most of the hamsters developed classical clinical signs of prion disease and typical disease-associated brain changes. Our findings suggest that prion contamination of surfaces commonly present in the environment can be a source of disease transmission, thus expanding our understanding of the mechanisms for prion spreading in nature.
Topics: Agriculture; Animals; Environment; PrPC Proteins; PrPSc Proteins; Prion Diseases; Surface Properties
PubMed: 29330304
DOI: 10.1074/jbc.M117.810747 -
Nature Reviews. Neurology Feb 2015Prion diseases are typically recognized as rapidly progressive dementing illnesses that also feature myoclonus and cerebellar ataxia. Several families have now been... (Review)
Review
Prion diseases are typically recognized as rapidly progressive dementing illnesses that also feature myoclonus and cerebellar ataxia. Several families have now been described with a late-onset hereditary sensory and autonomic neuropathy caused by truncation of prion protein (PrP), and associated with systemic amyloidosis, which was a profoundly unexpected phenotype. The chronic symptoms of this disorder, termed PrP systemic amyloidosis, can be very disabling, and are comparable to familial amyloid polyneuropathy (FAP) caused by transthyretin mutations. Patients require symptomatic therapies directed towards control of nausea, diarrhoea, incontinence, neuropathic pain and postural hypotension. Although the potential transmissibility of this new prion disease is probably extremely low, we advocate PrP gene analysis before biopsy in the investigation of peripheral and autonomic neuropathies, or for patients with unexplained diarrhoea and neuropathy. Prion diseases and the FAPs both display prominent effects of mutation type on clinical presentation and patterns of pathology-a fascinating but unexplained observation. Several neurodegenerative diseases associated with central protein misfolding, such as Huntington and Parkinson diseases, also have under-recognized peripheral components. Most of the familial amyloidoses can be explained by known gene mutations, but amino acid variants in proteins involved in other central neurodegenerative diseases might direct the initial pathology to the periphery.
Topics: Amyloidosis; Diagnosis, Differential; Humans; Immunoglobulin Light-chain Amyloidosis; Prion Diseases
PubMed: 25623792
DOI: 10.1038/nrneurol.2014.263 -
Acta Neuropathologica Jan 2011Human prion diseases are rare neurodegenerative disorders related to prion protein misfolding that can occur as sporadic, familial or acquired forms. In comparison to... (Review)
Review
Human prion diseases are rare neurodegenerative disorders related to prion protein misfolding that can occur as sporadic, familial or acquired forms. In comparison to other more common neurodegenerative disorders, prion diseases show a wider range of phenotypic variation and largely transmit to experimental animals, a feature that led to the isolation and characterization of different strains of the transmissible agent or prion with distinct biological properties. Biochemically distinct PrP(Sc) types have been demonstrated which differ in their size after proteinase cleavage, glycosylation pattern, and possibly other features related to their conformation. These PrP(Sc) types, possibly enciphering the prion strains, together with the naturally occurring polymorphism at codon 129 in the prion protein gene have a major influence on the disease phenotype. In the sporadic form, the most common but perhaps least understood form of human prion disease, there are at least six major combinations of codon 129 genotype and prion protein isotype, which are significantly related to distinctive clinical-pathological subgroups of the disease. In this review, we provide an update on the current knowledge and classification of the disease subtypes of the sporadic human prion diseases as defined by molecular features and pathological changes. Furthermore, we discuss the molecular basis of phenotypic variability taking into account the results of recent transmission studies that shed light on the extent of prion strain variation in humans.
Topics: Animals; Codon; Diagnosis, Differential; Disease Models, Animal; Forecasting; Humans; Phenotype; Polymorphism, Genetic; PrPC Proteins; PrPSc Proteins; Prion Diseases
PubMed: 21107851
DOI: 10.1007/s00401-010-0779-6 -
Molecular Imaging and Biology Apr 2024Prion diseases are rare, rapidly progressive, and fatal incurable degenerative brain disorders caused by the misfolding of a normal protein called PrPC into an abnormal... (Review)
Review
Prion diseases are rare, rapidly progressive, and fatal incurable degenerative brain disorders caused by the misfolding of a normal protein called PrPC into an abnormal protein called PrPSc. Their highly variable clinical presentation mimics various degenerative and non-degenerative brain disorders, making diagnosis a significant challenge for neurologists. Currently, definitive diagnosis relies on post-mortem examination of nervous tissue to detect the pathogenic prion protein. The current diagnostic criteria are limited. While structural magnetic resonance imaging (MRI) remains the gold standard imaging modality for Creutzfeldt-Jakob disease (CJD) diagnosis, positron emission tomography (PET) using fluorine-fluorodeoxyglucose (F-FDG) and other radiotracers have demonstrated promising potential in the diagnostic assessment of prion disease. In this context, a comprehensive and updated review exclusively focused on PET imaging in prion diseases is still lacking. We review the current value of PET imaging with F-FDG and non-FDG tracers in the diagnostic management of prion diseases. From the collected data, F-FDG PET mainly reveals cortical and subcortical hypometabolic areas in prion disease, although fails to identify typical pattern or laterality abnormalities to differentiate between genetic and sporadic prion diseases. Although the rarity of prion diseases limits the establishment of a definitive hypometabolism pattern, this review reveals some more prevalent F-FDG patterns associated with each disease subtype. Interestingly, in both sporadic and genetic prion diseases, the hippocampus does not show significant glucose metabolism alterations, appearing as a useful sign in the differential diagnosis with other neurodegenerative disease. In genetic prion disease forms, PET abnormality precedes clinical manifestation. Discordant diagnostic value for amyloid tracers among different prion disease subtypes was observed, needing further investigation. PET has emerged as a potential valuable tool in the diagnostic armamentarium for CJD. Its ability to visualize functional and metabolic brain changes provides complementary information to structural MRI, aiding in the early detection and confirmation of CJD.
Topics: Humans; Fluorodeoxyglucose F18; Neurodegenerative Diseases; Radiopharmaceuticals; Positron-Emission Tomography; Prion Diseases; Creutzfeldt-Jakob Syndrome; Brain
PubMed: 38302686
DOI: 10.1007/s11307-024-01895-0 -
PloS One 2015Prion diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep are fatal neurodegenerative diseases for...
Prion diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep are fatal neurodegenerative diseases for which there is no effective treatment. The pathology of these diseases involves the conversion of a protease sensitive form of the cellular prion protein (PrPC) into a protease resistant infectious form (PrPsc or PrPres). Both in vitro (cell culture and cell free conversion assays) and in vivo (animal) studies have demonstrated the strong dependence of this conversion process on protein sequence homology between the initial prion inoculum and the host's own cellular prion protein. The presence of non-homologous (heterologous) proteins is often inhibitory to this conversion process. We hypothesize that the presence of heterologous prion proteins from one species might therefore constitute an effective treatment for prion disease in another species. To test this hypothesis, we infected mice intracerebrally with murine adapted RML-Chandler scrapie and treated them with heterologous prion protein (purified bacterially expressed recombinant hamster prion protein) or vehicle alone. Treated animals demonstrated reduced disease associated pathology, decreased accumulation of protease-resistant disease-associated prion protein, with delayed onset of clinical symptoms and motor deficits. This was concomitant with significantly increased survival times relative to mock-treated animals. These results provide proof of principle that recombinant hamster prion proteins can effectively and safely inhibit prion disease in mice, and suggest that hamster or other non-human prion proteins may be a viable treatment for prion diseases in humans.
Topics: Animals; Cells, Cultured; Cricetinae; Disease Models, Animal; Disease Progression; Female; Gliosis; Mice; Mice, Inbred C57BL; PrPC Proteins; Prion Diseases; Recombinant Proteins; Scrapie; Treatment Outcome
PubMed: 26134409
DOI: 10.1371/journal.pone.0131993