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Advances in Neurobiology 2017Prion diseases are a group of invariably fatal and transmissible neurodegenerative disorders that are associated with the misfolding of the normal cellular prion... (Review)
Review
Prion diseases are a group of invariably fatal and transmissible neurodegenerative disorders that are associated with the misfolding of the normal cellular prion protein, with the misfolded conformers constituting an infectious unit referred to as a "prion". Prions can spread within an affected organism by directly propagating this misfolding within and between cells and can transmit disease between animals of the same and different species. Prion diseases have a range of clinical phenotypes in humans and animals, with a principle determinant of this attributed to different conformations of the misfolded protein, referred to as prion strains. This chapter will describe the different clinical manifestations of prion diseases, the evidence that these diseases can be transmitted by an infectious protein and how the misfolding of this protein causes disease.
Topics: Animals; Astrocytes; Cattle; Creutzfeldt-Jakob Syndrome; Deer; Encephalopathy, Bovine Spongiform; Gliosis; Humans; Hyperplasia; Hypertrophy; Prion Diseases; Prion Proteins; Protein Aggregation, Pathological; Protein Folding; Scrapie; Wasting Disease, Chronic
PubMed: 28674988
DOI: 10.1007/978-3-319-57193-5_13 -
Handbook of Clinical Neurology 2017The human prion diseases comprise Creutzfeldt-Jakob disease, variably protease-sensitive prionopathy, Gerstmann-Sträussler-Scheinker disease, fatal familial insomnia,... (Review)
Review
The human prion diseases comprise Creutzfeldt-Jakob disease, variably protease-sensitive prionopathy, Gerstmann-Sträussler-Scheinker disease, fatal familial insomnia, and kuru. Each is a uniformly fatal rare neurodegenerative disease in which conformational changes in the prion protein are thought to be the central pathophysiologic event. The majority of cases of human prion diseases occur worldwide in the form of sporadic Creutzfeldt-Jakob disease and a minority of around 10-15% are associated with mutations of the prion protein gene, termed PRNP, in the forms of genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. Prion diseases are also transmissible and occur in iatrogenic and zoonotic forms (iatrogenic Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease respectively), adding a public health dimension to their management. Despite having a high public profile, human prion diseases are both rare and heterogeneous in their clinicopathologic phenotype, sometimes making a diagnosis challenging. A combined clinical, genetic, neuropathologic, and biochemical approach to diagnosis is therefore essential. The intensive study of these diseases continues to inform on neurodegenerative mechanisms and the role of protein misfolding in more common neurodegenerative diseases such as Parkinson disease and Alzheimer disease.
Topics: Animals; Central Nervous System; Humans; Neurochemistry; Neuropathology; Prion Diseases
PubMed: 28987186
DOI: 10.1016/B978-0-12-802395-2.00028-6 -
Current Opinion in Infectious Diseases Jun 2019Prion diseases are rapidly progressive neurodegenerative conditions that can be difficult to diagnose and are transmissible under specific circumstances. The authors... (Review)
Review
PURPOSE OF REVIEW
Prion diseases are rapidly progressive neurodegenerative conditions that can be difficult to diagnose and are transmissible under specific circumstances. The authors will provide background regarding prion disease and focus on diagnostic tools.
RECENT FINDINGS
Prion disease is caused by misfolded prion protein. The three possible causes of prion disease include sporadic (85%), genetic (10-15%), and acquired (<1%). Acquired prion diseases include kuru, iatrogenic, and variant Creutzfeldt-Jakob disease. Prion diseases differ in their clinical manifestation, neuropathology, and diagnostic test results. A variety of recent diagnostic tools have evolved that allow more reliable antemortem diagnosis of prion disease such as brain MRI and cerebrospinal fluid real-time quaking-induced conversion. Special infectivity guidelines must be followed when dealing with central nervous system tissue, but only standard precautions are needed for routine clinical care of patients with prion disease.
SUMMARY
The only way to definitely diagnose prion disease and determine its type is via neuropathologic examination. However, brain MRI and cerebrospinal fluid real-time quaking-induced conversion have drastically increased diagnostic accuracy and are important tests to use when evaluating patients with suspected prion disease.
Topics: Brain; Cerebrospinal Fluid; Diagnostic Tests, Routine; Humans; Magnetic Resonance Imaging; Prion Diseases; Prion Proteins
PubMed: 31008724
DOI: 10.1097/QCO.0000000000000552 -
Handbook of Clinical Neurology 2018Arguably the most important goal of prion research is the discovery of a safe and effective treatment for the human diseases. The final stages of the pathway to develop...
Arguably the most important goal of prion research is the discovery of a safe and effective treatment for the human diseases. The final stages of the pathway to develop a treatment require clinical trials. Choices about how a trial is designed and conducted have a large impact on the chances of success. The gold-standard large randomized double-blind placebo-controlled study, which minimizes sources of bias and has been incredibly successful in other diseases, has been hard to achieve in Creutzfeldt-Jakob disease principally because of the rarity and rapidity of the clinical syndrome. To date, clinical trials have been restricted to repurposed compounds, doxycycline, quinacrine, pentosan polysulfate (PPS), and flupertine. In most cases, these trials have used survival as an endpoint, which, whilst clearcut, has limitations. Biomarkers have played a strong role in diagnosis and entry criteria, but only a limited role as secondary outcome measures. Recent developments suggest some possible improvements in trial design by use of new outcome measures that have more favorable properties, and biomarkers of neuronal damage and/or prion seeding activity. Alternative patient populations, including those at risk of genetic forms of prion disease, warrant more consideration. In the future, improved trial designs will be employed to test compounds designed specifically to treat prion diseases.
Topics: Clinical Trials as Topic; Drug Discovery; Humans; Prion Diseases
PubMed: 29887150
DOI: 10.1016/B978-0-444-63945-5.00024-6 -
Advances in Experimental Medicine and... 2020Prion disease, also known as transmissible spongiform encephalopathy (TES), is a fatal neurodegenerative disease caused by prion protein. The most important pathogenesis... (Review)
Review
Prion disease, also known as transmissible spongiform encephalopathy (TES), is a fatal neurodegenerative disease caused by prion protein. The most important pathogenesis is related to changes in the conformation of cellular prion proteins (PrP). The histopathological features of prion disease are spongiform degeneration, neuronal deficiency, glial activation and the deposition of amyloid-like PrP. Cellular prion protein, ubiquitously expressed in the brain and other tissues, is transformed into the PrP (PrP) isoform in the prion disease. In this chapter, we summarize the research progresses of prion disease, the structural organization and normal function of PrP in the central nervous system. Moreover, the formation and transmissibility of prion aggregations (PrP) were also included. But we mainly focused on the function of PrP in autophagy. Several autophagic-related markers, such as p62 and LC3, are significantly upregulated in models of prion disease. Recent advances in the autophagic invention in prion disease and several pharmaceutical targets of autophagy were reviewed in this chapter. It is necessary to understand how the prion protein spread, transport and recycle, and what is the relationship between the clearance and autophagy.
Topics: Autophagy; Humans; Prion Diseases; Prion Proteins
PubMed: 32671739
DOI: 10.1007/978-981-15-4272-5_4 -
Cell and Tissue Research Apr 2023Prion diseases are devastating neurodegenerative diseases caused by the structural conversion of the normally benign prion protein (PrP) to an infectious,... (Review)
Review
Prion diseases are devastating neurodegenerative diseases caused by the structural conversion of the normally benign prion protein (PrP) to an infectious, disease-associated, conformer, PrP. After decades of intense research, much is known about the self-templated prion conversion process, a phenomenon which is now understood to be operative in other more common neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In this review, we provide the current state of knowledge concerning a relatively poorly understood aspect of prion diseases: mechanisms of neurotoxicity. We provide an overview of proposed functions of PrP and its interactions with other extracellular proteins in the central nervous system, in vivo and in vitro models used to delineate signaling events downstream of prion propagation, the application of omics technologies, and the emerging appreciation of the role played by non-neuronal cell types in pathogenesis.
Topics: Humans; Prions; Prion Diseases; Prion Proteins; Neurodegenerative Diseases; Alzheimer Disease
PubMed: 36070155
DOI: 10.1007/s00441-022-03683-0 -
Cold Spring Harbor Perspectives in... Dec 2016Prion diseases affect a wide range of mammal species and are caused by a misfolded self-propagating isoform (PrP) of the normal prion protein (PrP). Distinct strains of... (Review)
Review
Prion diseases affect a wide range of mammal species and are caused by a misfolded self-propagating isoform (PrP) of the normal prion protein (PrP). Distinct strains of prions exist and are operationally defined by differences in a heritable phenotype under controlled experimental transmission conditions. Prion strains can differ in incubation period, clinical signs of disease, tissue tropism, and host range. The mechanism by which a protein-only pathogen can encode strain diversity is only beginning to be understood. The prevailing hypothesis is that prion strain diversity is encoded by strain-specific conformations of PrP; however, strain-specific cellular cofactors have been identified in vitro that may also contribute to prion strain diversity. Although much progress has been made on understanding the etiological agent of prion disease, the relationship between the strain-specific properties of PrP and the resulting phenotype of disease in animals is poorly understood.
Topics: Animals; Brain; Cattle; Humans; Phenotype; PrPSc Proteins; Prion Diseases; Protein Conformation; Sheep; Species Specificity
PubMed: 27908925
DOI: 10.1101/cshperspect.a024349 -
International Journal of Molecular... Feb 2021Neuroinflammation, typically manifest as microglial activation and astrogliosis accompanied by transcriptomic alterations, represents a common hallmark of various... (Review)
Review
Neuroinflammation, typically manifest as microglial activation and astrogliosis accompanied by transcriptomic alterations, represents a common hallmark of various neurodegenerative conditions including prion diseases. Microglia play an overall neuroprotective role in prion disease, whereas reactive astrocytes with aberrant phenotypes propagate prions and contribute to prion-induced neurodegeneration. The existence of heterogeneous subpopulations and dual functions of microglia and astrocytes in prion disease make them potential targets for therapeutic intervention. A variety of neuroinflammation-related molecules are involved in prion pathogenesis. Therapeutics targeting neuroinflammation represents a novel approach to combat prion disease. Deciphering neuroinflammation in prion disease will deepen our understanding of pathogenesis of other neurodegenerative disorders.
Topics: Animals; Brain; Chemokines; Cytokines; Gliosis; Humans; Inflammation; Microglia; Phagocytosis; Prion Diseases; Toll-Like Receptors
PubMed: 33672129
DOI: 10.3390/ijms22042196 -
Handbook of Clinical Neurology 2018Variably protease-sensitive prionopathy (VPSPr), originally identified in 2008, was further characterized and renamed in 2010. Thirty-seven cases of VPSPr have been...
Variably protease-sensitive prionopathy (VPSPr), originally identified in 2008, was further characterized and renamed in 2010. Thirty-seven cases of VPSPr have been reported to date, consistent with estimated prevalence of 0.7-1.7% of all sporadic prion diseases. The lack of gene mutations establishes VPSPr as a sporadic form of human prion diseases, along with sporadic Creutzfeldt-Jakob disease (sCJD) and sporadic fatal insomnia. Like sCJD, VPSPr affects patients harboring any of the three genotypes, MM, MV, and VV at the prion protein (PrP) gene polymorphic codon 129, with VPSPr VV accounting for 65% of all VPSPr cases. Distinguishing clinical features include a median 2-year duration and presentation with psychiatric signs, speech/language impairment, or cognitive decline. Neuropathology comprises moderate spongiform degeneration, PrP amyloid miniplaques, and a target-like or plaque-like PrP deposition. The abnormal PrP associated with VPSPr typically forms an electrophoretic profile of five to seven bands (according to the antibody) presenting variable protease resistance depending on the 129 genotype. The familial prion disease associated with the V180I PrP gene mutation which harbors an abnormal PrP with similar electrophoretic profile might serve as a model for VPSPr. Transmission to animals has definitively established VPSPr as a prion disease. Because of its recent identification, rarity, and the elusiveness of its abnormal PrP, VPSPr remains largely understudied.
Topics: Animals; Cognition Disorders; Humans; Hydrocephalus, Normal Pressure; PrPSc Proteins; Prion Diseases; Proteolysis; Speech Disorders
PubMed: 29887135
DOI: 10.1016/B978-0-444-63945-5.00010-6 -
Cell and Tissue Research Apr 2023
Topics: Humans; Prion Diseases; Prions
PubMed: 36918429
DOI: 10.1007/s00441-023-03760-y