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Handbook of Clinical Neurology 2018The cellular prion protein, PrP, is a small, cell surface glycoprotein with a function that is currently somewhat ill defined. It is also the key molecule involved in... (Review)
Review
The cellular prion protein, PrP, is a small, cell surface glycoprotein with a function that is currently somewhat ill defined. It is also the key molecule involved in the family of neurodegenerative disorders called transmissible spongiform encephalopathies, which are also known as prion diseases. The misfolding of PrP to a conformationally altered isoform, designated PrP, is the main molecular process involved in pathogenesis and appears to precede many other pathologic and clinical manifestations of disease, including neuronal loss, astrogliosis, and cognitive loss. PrP is also believed to be the major component of the infectious "prion," the agent responsible for disease transmission, and preparations of this protein can cause prion disease when inoculated into a naïve host. Thus, understanding the biochemical and biophysical properties of both PrP and PrP, and ultimately the mechanisms of their interconversion, is critical if we are to understand prion disease biology. Although entire books could be devoted to research pertaining to the protein, herein we briefly review the state of knowledge of prion biochemistry, including consideration of prion protein structure, function, misfolding, and dysfunction.
Topics: Animals; Humans; Prion Diseases; Prion Proteins; Protein Folding
PubMed: 29887138
DOI: 10.1016/B978-0-444-63945-5.00002-7 -
Journal of Cell Science Sep 2021Prion diseases are neurodegenerative disorders caused by conformational conversion of the cellular prion protein (PrPC) into scrapie prion protein (PrPSc). As the main...
Prion diseases are neurodegenerative disorders caused by conformational conversion of the cellular prion protein (PrPC) into scrapie prion protein (PrPSc). As the main component of prion, PrPSc acts as an infectious template that recruits and converts normal cellular PrPC into its pathogenic, misfolded isoform. Intriguingly, the phenomenon of prionoid, or prion-like, spread has also been observed in many other disease-associated proteins, such as amyloid β (Aβ), tau and α-synuclein. This Cell Science at a Glance and the accompanying poster highlight recently described physiological roles of prion protein and the advanced understanding of pathogenesis of prion disease they have afforded. Importantly, prion protein may also be involved in the pathogenesis of other neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Therapeutic studies of prion disease have also exploited novel strategies to combat these devastating diseases. Future studies on prion protein and prion disease will deepen our understanding of the pathogenesis of a broad spectrum of neurodegenerative conditions.
Topics: Amyloid beta-Peptides; Animals; Prion Diseases; Prion Proteins; Prions; alpha-Synuclein
PubMed: 34472604
DOI: 10.1242/jcs.245605 -
Journal of Visualized Experiments : JoVE May 2023Abnormal prion proteins (PrP) are the disease-associated isoform of cellular prion protein and diagnostic markers of transmissible spongiform encephalopathies (TSEs)....
Abnormal prion proteins (PrP) are the disease-associated isoform of cellular prion protein and diagnostic markers of transmissible spongiform encephalopathies (TSEs). These neurodegenerative diseases affect humans and several animal species and include scrapie, zoonotic bovine spongiform encephalopathy (BSE), chronic wasting disease of cervids (CWD), and the newly identified camel prion disease (CPD). Diagnosis of TSEs relies on immunodetection of PrP by application of both immunohistochemistry (IHC) and western immunoblot methods (WB) on encephalon tissues, namely, the brainstem (obex level). IHC is a widely used method that uses primary antibodies (monoclonal or polyclonal) against antigens of interest in cells of a tissue section. The antibody-antigen binding can be visualized by a color reaction that remains localized in the area of the tissue or cell where the antibody was targeted. As such, in prion diseases, as in other fields of research, the immunohistochemistry techniques are not solely used for diagnostic purposes but also in pathogenesis studies. Such studies involve detecting the PrP patterns and types from those previously described to identify the new prion strains. As BSE can infect humans, it is recommended that biosafety laboratory level-3 (BSL-3) facilities and/or practices are used to handle cattle, small ruminants, and cervid samples included in the TSE surveillance. Additionally, containment and prion-dedicated equipment are recommended, whenever possible, to limit contamination. The PrP IHC procedure consists of a formic acid epitope-demasking step also acting as a prion inactivation measure, as formalin-fixed and paraffin-embedded tissues used in this technique remain infectious. When interpreting the results, care must be taken to distinguish non-specific immunolabeling from target labeling. For this purpose, it is important to recognize artifacts of immunolabeling obtained in known TSE-negative control animals to differentiate those from specific PrP immunolabeling types, which can vary between TSE strains, host species, and prnp genotype, further described herein.
Topics: Animals; Sheep; Cattle; Humans; Prion Proteins; Immunohistochemistry; Prion Diseases; Scrapie; Prions; Encephalopathy, Bovine Spongiform; Wasting Disease, Chronic; Deer
PubMed: 37212578
DOI: 10.3791/64560 -
ACS Chemical Neuroscience Mar 2018Prion diseases are phenotypically diverse, transmissible, neurodegenerative disorders affecting both animals and humans. Misfolding of the normal prion protein (PrP)... (Review)
Review
Prion diseases are phenotypically diverse, transmissible, neurodegenerative disorders affecting both animals and humans. Misfolding of the normal prion protein (PrP) into disease-associated conformers (PrP) is considered the critical etiological event underpinning prion diseases, with such misfolded isoforms linked to both disease transmission and neurotoxicity. Although important advances in our understanding of prion biology and pathogenesis have occurred over the last 3-4 decades, many fundamental questions remain to be resolved, including consensus regarding the principal pathways subserving neuronal dysfunction, as well as detailed biophysical characterization of PrP species transmitting disease and/or directly associated with neurotoxicity. In vivo and in vitro models have been, and remain, critical to furthering our understanding across many aspects of prion disease patho-biology. Prion animal models are arguably the most authentic in vivo models of neurodegeneration that exist and have provided valuable and multifarious insights into pathogenesis; however, they are expensive and time-consuming, and it can be problematic to clearly discern evidence of direct PrP neurotoxicity in the overall context of pathogenesis. In vitro models, in contrast, generally offer greater tractability and appear more suited to assessments of direct acute neurotoxicity but have until recently been relatively simplistic, and overall there remains a relative paucity of validated, biologically relevant models with heightened reliability as far as translational insights, contributing to difficulties in redressing our knowledge gaps in prion disease pathogenesis. In this review, we provide an overview of the spectrum and methodological diversity of in vivo and in vitro models of prion acute toxicity, as well as the pathogenic insights gained from these studies.
Topics: Animals; Humans; Models, Biological; Neurons; Neurotoxicity Syndromes; PrPSc Proteins; Prion Diseases; Prions
PubMed: 29393619
DOI: 10.1021/acschemneuro.7b00517 -
Genetics in Medicine : Official Journal... Oct 2022Prion disease is a rare, fatal, and often rapidly progressive neurodegenerative disease. Ten to fifteen percent of cases are caused by autosomal dominant... (Review)
Review
Prion disease is a rare, fatal, and often rapidly progressive neurodegenerative disease. Ten to fifteen percent of cases are caused by autosomal dominant gain-of-function variants in the prion protein gene, PRNP. Rarity and phenotypic variability complicate diagnosis, often obscuring family history and leaving families unprepared for the genetic implications of an index case. Several recent developments inspire this update in best practices for prion disease genetic counseling. A new prion-detection assay has transformed symptomatic diagnosis. Meanwhile, penetrance, age of onset, and duration of illness have been systematically characterized across PRNP variants in a global cohort. Clinically, the traditional genotype-phenotype correlation has weakened over time, and the term genetic prion disease may now better serve providers than the historical subtypes Creutzfeldt-Jakob disease, fatal familial insomnia, and Gerstmann-Sträussler-Scheinker disease. Finally, in the age of genetically targeted therapies, clinical trials for prion disease are being envisaged, and healthy at-risk individuals may be best positioned to benefit. Such individuals need to be able to access clinical services for genetic counseling and testing. Thus, this update on the genetics of prion disease and best practices for genetic counseling for this disease aims to provide the information needed to expand genetic counseling services.
Topics: Genetic Counseling; Humans; Neurodegenerative Diseases; Prion Diseases; Prion Proteins; Prions
PubMed: 35819418
DOI: 10.1016/j.gim.2022.06.003 -
The Journal of Biological Chemistry Aug 2022The structures of prion protein (PrP)-based mammalian prions have long been elusive. However, cryo-EM has begun to reveal the near-atomic resolution structures of fully... (Review)
Review
The structures of prion protein (PrP)-based mammalian prions have long been elusive. However, cryo-EM has begun to reveal the near-atomic resolution structures of fully infectious ex vivo mammalian prion fibrils as well as relatively innocuous synthetic PrP amyloids. Comparisons of these various types of PrP fibrils are now providing initial clues to structural features that correlate with pathogenicity. As first indicated by electron paramagnetic resonance and solid-state NMR studies of synthetic amyloids, all sufficiently resolved PrP fibrils of any sort (n > 10) have parallel in-register intermolecular β-stack architectures. Cryo-EM has shown that infectious brain-derived prion fibrils of the rodent-adapted 263K and RML scrapie strains have much larger ordered cores than the synthetic fibrils. These bona fide prion strains share major structural motifs, but the conformational details and the overall shape of the fibril cross sections differ markedly. Such motif variations, as well as differences in sequence within the ordered polypeptide cores, likely contribute to strain-dependent templating. When present, N-linked glycans and glycophosphatidylinositol (GPI) anchors project outward from the fibril surface. For the mouse RML strain, these posttranslational modifications have little effect on the core structure. In the GPI-anchored prion structures, a linear array of GPI anchors along the twisting fibril axis appears likely to bind membranes in vivo, and as such, may account for pathognomonic membrane distortions seen in prion diseases. In this review, we focus on these infectious prion structures and their implications regarding prion replication mechanisms, strains, transmission barriers, and molecular pathogenesis.
Topics: Amyloid; Animals; Biology; Mammals; Mice; Prion Diseases; Prion Proteins; Prions; Scrapie; Sheep
PubMed: 35752366
DOI: 10.1016/j.jbc.2022.102181 -
Current Opinion in Pharmacology Feb 2019Prion-related encephalopathies or transmissible spongiform encephalopathies (TSEs) are a group of rare progressive neurodegenerative disorders that are invariably fatal... (Review)
Review
Prion-related encephalopathies or transmissible spongiform encephalopathies (TSEs) are a group of rare progressive neurodegenerative disorders that are invariably fatal with often only six months elapsing from diagnosis to patient death. This makes the development of effective therapeutic strategies challenging. Nonetheless, compounds have been identified in animal models of TSE that prolong survival and, in some instances, eradicate the disease. These have been tested in the clinic, although with modest or negative outcomes. While little progress has been made over the last decade, new findings that include the ability to identify prion aggregates at low levels in biological fluids and cells may lead to the development of early-stage biomarkers for TSE. An increased focus on immunotherapeutic approaches to TSE may result in the development of novel preventive approaches for TSE.
Topics: Animals; Doxycycline; Humans; Immunotherapy; Prion Diseases
PubMed: 31108459
DOI: 10.1016/j.coph.2019.04.019 -
Brain Research Oct 2016Prion diseases are fatal neurodegenerative disorders that include scrapie of sheep, bovine spongiform encephalopathy of cattle, chronic wasting disease of cervids, and... (Review)
Review
Prion diseases are fatal neurodegenerative disorders that include scrapie of sheep, bovine spongiform encephalopathy of cattle, chronic wasting disease of cervids, and Creutzfeldt-Jakob disease (CJD) of humans. The etiology for prion diseases can be infectious, sporadic, or hereditary. However, the common denominator for all types is the formation of a transmissible agent composed of a β-sheet-rich, misfolded version of the host-encoded prion protein (PrP), known as PrP. PrP self-replicates through a template-assisted process that converts the α-helical conformation of PrP into the disease-associated isoform. In parallel with PrP accumulation, spongiform change is pathologically observed in the central nervous system, where "holes" appear because of massive neuronal death. Here, we review the cellular pathways triggered in response to PrP formation and accumulation. Available data suggest that neuronal dysfunction and death may be caused by what originates as a cellular pro-survival response to chronic PrP accumulation. We also discuss what is known about the complex cross-talk between the endoplasmic reticulum stress components and the quality control pathways. Better knowledge about these processes may lead to innovative therapeutic strategies based on manipulating the stress response and its consequences for neurodegeneration. This article is part of a Special Issue entitled SI:ER stress.
Topics: Animals; Endoplasmic Reticulum Stress; Humans; Prion Diseases; Prion Proteins; Signal Transduction
PubMed: 27060771
DOI: 10.1016/j.brainres.2016.04.009 -
Epilepsy & Behavior : E&B Feb 2021Epileptic seizures have been described as one feature of prion diseases, but are an unusual clinical presentation. The aim of this narrative Review was to summarize... (Review)
Review
Epileptic seizures have been described as one feature of prion diseases, but are an unusual clinical presentation. The aim of this narrative Review was to summarize current knowledge of epileptic seizures in the various forms of prion diseases, from a clinical perspective. Examination of the published literature identified no systematic studies; the evidence base is largely anecdotal, consisting mainly of case studies and small case series. Hence, uncertainty prevails as to seizure frequency, semiology, treatment, and pathogenesis in prion diseases. Seizures probably occur in around 10% of sporadic cases but less frequently in iatrogenic and familial forms, with the possible exception of the E200K mutation. The literature suggests a predominance of focal motor and nonconvulsive status epilepticus. Electroencephalographic accompaniments include periodic lateralized or generalized periodic epileptiform discharges (PLEDs, GPEDs), sometimes predating the more typical periodic sharp wave complexes. There are no convincing accounts of successful antiepileptic drug therapy. The underlying mechanisms of epileptogenesis in prion diseases may include loss of cellular prion protein function (PrP) and aggregation of abnormally folded prion protein (PrP). The need for systematic studies and clinical trials to expand the evidence base surrounding epilepsy and prion diseases is evident.
Topics: Creutzfeldt-Jakob Syndrome; Epilepsy; Humans; Prion Diseases; Prions; Seizures
PubMed: 33309427
DOI: 10.1016/j.yebeh.2020.107630 -
Journal of Enzyme Inhibition and... Dec 2023Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrP) that forms insoluble...
Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrP) that forms insoluble amyloids to impair brain function. PrP interacts with the non-pathogenic, cellular prion protein (PrP) and facilitates conversion into a nascent misfolded isoform. Several small molecules have been reported to inhibit the aggregation of PrP but no pharmacological intervention was well established thus far. We, here, report that acylthiosemicarbazides inhibit the prion aggregation. Compounds and showed almost perfect inhibition (EC = 5 µM) in prion aggregation formation assay. The activity was further confirmed by atomic force microscopy, semi-denaturing detergent agarose gel electrophoresis and real-time quaking induced conversion assay (EC = 0.9 and 2.8 µM, respectively). These compounds also disaggregated pre-existing aggregates and one of them decreased the level of PrP in cultured cells with permanent prion infection, suggesting their potential as a treatment platform. In conclusion, hydroxy-2-naphthoylthiosemicarbazides can be an excellent scaffold for the discovery of anti-prion therapeutics.
Topics: Humans; Prions; Prion Proteins; Brain; Prion Diseases; Cells, Cultured
PubMed: 36950944
DOI: 10.1080/14756366.2023.2191164