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Seminars in Neurology Aug 2019Prion diseases are a phenotypically diverse set of disorders characterized by protease-resistant abnormally shaped proteins known as prions. There are three main groups... (Review)
Review
Prion diseases are a phenotypically diverse set of disorders characterized by protease-resistant abnormally shaped proteins known as prions. There are three main groups of prion diseases, termed sporadic (Creutzfeldt-Jakob disease [CJD], sporadic fatal insomnia, and variably protease-sensitive prionopathy), genetic (genetic CJD, fatal familial insomnia, and Gerstmann-Straussler-Scheinker syndrome), and acquired (kuru, variant CJD, and iatrogenic CJD). This article will review the pathophysiology, genetics, clinical presentations, and diagnostic challenges in patients with prion disease. Case discussions, images, and tables will be used to highlight important characteristics of prion disease and prion mimics.
Topics: Aged; Animals; Creutzfeldt-Jakob Syndrome; Diagnosis, Differential; Humans; Male; Middle Aged; Prion Diseases; Wernicke Encephalopathy
PubMed: 31533183
DOI: 10.1055/s-0039-1687841 -
Annual Review of Pathology Jan 2019Prion diseases are rapidly progressive, incurable neurodegenerative disorders caused by misfolded, aggregated proteins known as prions, which are uniquely infectious.... (Review)
Review
Prion diseases are rapidly progressive, incurable neurodegenerative disorders caused by misfolded, aggregated proteins known as prions, which are uniquely infectious. Remarkably, these infectious proteins have been responsible for widespread disease epidemics, including kuru in humans, bovine spongiform encephalopathy in cattle, and chronic wasting disease in cervids, the latter of which has spread across North America and recently appeared in Norway and Finland. The hallmark histopathological features include widespread spongiform encephalopathy, neuronal loss, gliosis, and deposits of variably sized aggregated prion protein, ranging from small, soluble oligomers to long, thin, unbranched fibrils, depending on the disease. Here, we explore recent advances in prion disease research, from the function of the cellular prion protein to the dysfunction triggering neurotoxicity, as well as mechanisms underlying prion spread between cells. We also highlight key findings that have revealed new therapeutic targets and consider unanswered questions for future research.
Topics: Amyloid; Animals; Cattle; Deer; Humans; Neurodegenerative Diseases; Prion Diseases; Prion Proteins
PubMed: 30355150
DOI: 10.1146/annurev-pathmechdis-012418-013109 -
Cell and Tissue Research Apr 2023Prion diseases are fatal neurodegenerative conditions of humans and various vertebrate species that are transmissible between individuals of the same or different... (Review)
Review
Prion diseases are fatal neurodegenerative conditions of humans and various vertebrate species that are transmissible between individuals of the same or different species. A novel infectious moiety referred to as a prion is considered responsible for transmission of these conditions. Prion replication is believed to be the cause of the neurotoxicity that arises during prion disease pathogenesis. The prion hypothesis predicts that the transmissible prion agent consists of PrP, which is comprised of aggregated misfolded conformers of the normal host protein PrP. It is important to understand the biology of transmissible prions and to identify genetic modifiers of prion-induced neurotoxicity. This information will underpin the development of therapeutic and control strategies for human and animal prion diseases. The most reliable method to detect prion infectivity is by in vivo transmission in a suitable experimental host, which to date have been mammalian species. Current prion bioassays are slow, cumbersome and relatively insensitive to low titres of prion infectivity, and do not lend themselves to rapid genetic analysis of prion disease. Here, we provide an overview of our novel studies that have led to the establishment of Drosophila melanogaster, a genetically well-defined invertebrate host, as a sensitive, versatile and economically viable animal model for the detection of mammalian prion infectivity and genetic modifiers of prion-induced toxicity.
Topics: Animals; Humans; Drosophila; Drosophila melanogaster; Animals, Genetically Modified; Prion Diseases; Prions; Mammals
PubMed: 35092497
DOI: 10.1007/s00441-022-03586-0 -
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 -
Expert Opinion on Therapeutic Targets 2023Human prion diseases are heterogeneous, and often rapidly progressive, transmissible neurodegenerative disorders associated with misfolded prion protein (PrP)... (Review)
Review
INTRODUCTION
Human prion diseases are heterogeneous, and often rapidly progressive, transmissible neurodegenerative disorders associated with misfolded prion protein (PrP) aggregation and self-propagation. Despite their rarity, prion diseases comprise a broad spectrum of phenotypic variants determined at the molecular level by different conformers of misfolded PrP and host genotype variability. Moreover, they uniquely occur in idiopathic, genetically determined, and acquired forms with distinct etiologies.
AREA COVERED
This review provides an up-to-date overview of potential therapeutic targets in prion diseases and the main results obtained in cell and animal models and human trials. The open issues and challenges associated with developing effective therapies and informative clinical trials are also discussed.
EXPERT OPINION
Currently tested therapeutic strategies target the cellular PrP to prevent the formation of misfolded PrP or to favor its elimination. Among them, passive immunization and gene therapy with antisense oligonucleotides against prion protein mRNA are the most promising. However, the disease's rarity, heterogeneity, and rapid progression profoundly frustrate the successful undertaking of well-powered therapeutic trials and patient identification in the asymptomatic or early stage before the development of significant brain damage. Thus, the most promising therapeutic goal to date is preventing or delaying phenoconversion in carriers of pathogenic mutations by lowering prion protein expression.
Topics: Animals; Humans; Creutzfeldt-Jakob Syndrome; Prion Proteins; Prion Diseases; Prions
PubMed: 37334903
DOI: 10.1080/14728222.2023.2199923 -
Continuum (Minneapolis, Minn.) Dec 2015This article presents an update on the clinical aspects of human prion disease, including the wide spectrum of their presentations. (Review)
Review
PURPOSE OF REVIEW
This article presents an update on the clinical aspects of human prion disease, including the wide spectrum of their presentations.
RECENT FINDINGS
Prion diseases, a group of disorders caused by abnormally shaped proteins called prions, occur in sporadic (Jakob-Creutzfeldt disease), genetic (genetic Jakob-Creutzfeldt disease, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia), and acquired (kuru, variant Jakob-Creutzfeldt disease, and iatrogenic Jakob-Creutzfeldt disease) forms. This article presents updated information on the clinical features and diagnostic methods for human prion diseases. New antemortem potential diagnostic tests based on amplifying prions in order to detect them are showing very high specificity. Understanding of the diversity of possible presentations of human prion diseases continues to evolve, with some genetic forms progressing slowly over decades, beginning with dysautonomia and neuropathy and progressing to a frontal-executive dementia with pathology of combined prionopathy and tauopathy. Unfortunately, to date, all human prion disease clinical trials have failed to show survival benefit. A very rare polymorphism in the prion protein gene recently has been identified that appears to protect against prion disease; this finding, in addition to providing greater understanding of the prionlike mechanisms of neurodegenerative disorders, might lead to potential treatments.
SUMMARY
Sporadic Jakob-Creutzfeldt disease is the most common form of human prion disease. Genetic prion diseases, resulting from mutations in the prion-related protein gene (PRNP), are classified based on the mutation, clinical phenotype, and neuropathologic features and can be difficult to diagnose because of their varied presentations. Perhaps most relevant to this Continuum issue on neuroinfectious diseases, acquired prion diseases are caused by accidental transmission to humans, but fortunately, they are the least common form and are becoming rarer as awareness of transmission risk has led to implementation of measures to prevent such occurrences.
Topics: Humans; Prion Diseases
PubMed: 26633779
DOI: 10.1212/CON.0000000000000251 -
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 Lancet. Neurology Apr 2020Prion disease is a rare, fatal, and exceptionally rapid neurodegenerative disease. Although incurable, prion disease follows a clear pathogenic mechanism, in which a... (Review)
Review
Prion disease is a rare, fatal, and exceptionally rapid neurodegenerative disease. Although incurable, prion disease follows a clear pathogenic mechanism, in which a single gene gives rise to a single prion protein (PrP) capable of converting into the sole causal disease agent, the misfolded prion. As efforts progress to leverage this mechanistic knowledge toward rational therapies, a principal challenge will be the design of clinical trials. Previous trials in prion disease have been done in symptomatic patients who are often profoundly debilitated at enrolment. About 15% of prion disease cases are genetic, creating an opportunity for early therapeutic intervention to delay or prevent disease. Highly variable age of onset and absence of established prodromal biomarkers might render infeasible existing models for testing drugs before disease onset. Advancement of near-term targeted therapeutics could crucially depend on thoughtful design of rigorous presymptomatic trials.
Topics: Animals; Biomarkers; Humans; Neurodegenerative Diseases; Prion Diseases; Prion Proteins; Prions
PubMed: 32199098
DOI: 10.1016/S1474-4422(19)30403-X -
Progress in Molecular Biology and... 2020Human prion disease may present in a non-specific way and is often diagnosed at a relatively late stage of the illness. Until recently, clinical diagnosis has been... (Review)
Review
Human prion disease may present in a non-specific way and is often diagnosed at a relatively late stage of the illness. Until recently, clinical diagnosis has been supported by tests that are mostly non-specific and, sometimes, insensitive. Recent laboratory developments have led to a variety of tests that rely on a disease-specific mechanism. One test, the CSF RT-QuIC (Real-Time Quaking-Induced Conversion) test is very sensitive and specific for sporadic CJD and is now used in routine clinical practice. Other tests, based on other tissues, including blood and urine, have been developed and potentially could improve both clinical diagnostic accuracy and lead to earlier diagnosis. While there are yet no proven treatments for prion disease, any treatment to be developed will almost certainly require earlier diagnosis if therapeutic success is to be realized.
Topics: Humans; Practice Patterns, Physicians'; Prion Diseases; Prion Proteins
PubMed: 32958229
DOI: 10.1016/bs.pmbts.2020.07.006 -
Cell and Tissue Research Apr 2023Prion diseases, also known as transmissible spongiform encephalopathies, are caused by the accumulation of abnormal isoforms of the prion protein (scrapie isoform of the... (Review)
Review
Prion diseases, also known as transmissible spongiform encephalopathies, are caused by the accumulation of abnormal isoforms of the prion protein (scrapie isoform of the prion protein, PrPSc) in the central nervous system. Many compounds with anti-prion activities have been found using in silico screening, in vitro models, persistently prion-infected cell models, and prion-infected rodent models. Some of these compounds include several types of polymers. Although the inhibition or removal of PrPSc production is the main target of therapy, the unique features of prions, namely protein aggregation and assembly accompanied by steric structural transformation, may require different strategies for the development of anti-prion drugs than those for conventional therapeutics targeting enzyme inhibition, agonist ligands, or modulation of signaling. In this paper, we first overview the history of the application of polymers to prion disease research. Next, we describe the characteristics of each type of polymer with anti-prion activity. Finally, we discuss the common features of these polymers. Although drug delivery of these polymers to the brain is a challenge, they are useful not only as leads for therapeutic drugs but also as tools to explore the structure of PrPSc and are indispensable for prion disease research.
Topics: Animals; Sheep; Prion Proteins; Polymers; Prion Diseases; Scrapie; Prions
PubMed: 35307792
DOI: 10.1007/s00441-022-03604-1