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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 -
Microbiology and Molecular Biology... Sep 2017Chronic wasting disease (CWD) affects cervids and is the only known prion disease readily transmitted among free-ranging wild animal populations in nature. The... (Review)
Review
Chronic wasting disease (CWD) affects cervids and is the only known prion disease readily transmitted among free-ranging wild animal populations in nature. The increasing spread and prevalence of CWD among cervid populations threaten the survival of deer and elk herds in North America, and potentially beyond. This review focuses on prion ecology, specifically that of CWD, and the current understanding of the role that the environment may play in disease propagation. We recount the discovery of CWD, discuss the role of the environment in indirect CWD transmission, and consider potentially relevant environmental reservoirs and vectors. We conclude by discussing how understanding the environmental persistence of CWD lends insight into transmission dynamics and potential management and mitigation strategies.
Topics: Animals; Animals, Wild; Deer; Ecological and Environmental Phenomena; Prion Diseases; Prions; Soil; Wasting Disease, Chronic; Water
PubMed: 28566466
DOI: 10.1128/MMBR.00001-17 -
Arquivos de Neuro-psiquiatria Sep 2013Prion diseases are neurodegenerative illnesses due to the accumulation of small infectious pathogens containing protein but apparently lacking nucleic acid, which have... (Review)
Review
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.
Topics: Humans; Prion Diseases; Prions
PubMed: 24141515
DOI: 10.1590/0004-282X201301461 -
Cold Spring Harbor Perspectives in... Jul 2018Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease arising from the misfolding and accumulation of the protein α-synuclein in... (Review)
Review
Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease arising from the misfolding and accumulation of the protein α-synuclein in oligodendrocytes, where it forms glial cytoplasmic inclusions (GCIs). Several years of studying synthetic α-synuclein fibrils has provided critical insight into the ability of α-synuclein to template endogenous protein misfolding, giving rise to fibrillar structures capable of propagating from cell to cell. However, more recent studies with MSA-derived α-synuclein aggregates have shown that they have a similar ability to undergo template-directed propagation, like PrP prions. Almost 20 years after α-synuclein was discovered as the primary component of GCIs, α-synuclein aggregates isolated from MSA patient samples were shown to infect cultured mammalian cells and also to transmit neurological disease to transgenic mice. These findings argue that α-synuclein becomes a prion in MSA patients. In this review, we discuss the in vitro and in vivo data supporting the recent classification of MSA as a prion disease.
Topics: Animals; Cells, Cultured; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Multiple System Atrophy; Prion Diseases; Prions; alpha-Synuclein
PubMed: 28213437
DOI: 10.1101/cshperspect.a024588 -
Prion Dec 2022Prion diseases are a group of incurable zoonotic neurodegenerative diseases (NDDs) in humans and other animals caused by the prion proteins. The abnormal folding and... (Review)
Review
Prion diseases are a group of incurable zoonotic neurodegenerative diseases (NDDs) in humans and other animals caused by the prion proteins. The abnormal folding and aggregation of the soluble cellular prion proteins (PrP) into scrapie isoform (PrP) in the Central nervous system (CNS) resulted in brain damage and other neurological symptoms. Different therapeutic approaches, including stalling PrP to PrP conversion, increasing PrP removal, and PrP stabilization, for which a spectrum of compounds, ranging from organic compounds to antibodies, have been explored. Additionally, a non-PrP targeted drug strategy using serpin inhibitors has been discussed. Despite numerous scaffolds being screened for anti-prion activity , only a few were effective and unfortunately, almost none of them proved effective in the clinical studies, most likely due to toxicity and lack of permeability. Recently, encouraging results from a prion-protein monoclonal antibody, PRN100, were presented in the first human trial on CJD patients, which gives a hope for better future for the discovery of other new molecules to treat prion diseases. In this comprehensive review, we have re-visited the history and discussed various classes of anti-prion agents, their structure, mode of action, and toxicity. Understanding pathogenesis would be vital for developing future treatments for prion diseases. Based on the outcomes of existing therapies, new anti-prion agents could be identified/synthesized/designed with reduced toxicity and increased bioavailability, which could probably be effective in treating prion diseases.
Topics: Animals; Sheep; Humans; Prions; Prion Proteins; Prion Diseases; Scrapie
PubMed: 36515657
DOI: 10.1080/19336896.2022.2153551 -
Cell and Tissue Research Apr 2023Prion diseases are fatal infectious neurodegenerative disorders and prototypic conformational diseases, caused by the conformational conversion of the normal cellular... (Review)
Review
Prion diseases are fatal infectious neurodegenerative disorders and prototypic conformational diseases, caused by the conformational conversion of the normal cellular prion protein (PrP) into the pathological PrP isoform. Examples are scrapie in sheep and goat, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids, and Creutzfeldt-Jacob disease (CJD) in humans. There are no therapies available, and animal prion diseases like BSE and CWD can negatively affect the economy, ecology, animal health, and possibly human health. BSE is a confirmed threat to human health, and mounting evidence supports the zoonotic potential of CWD. CWD is continuously expanding in North America in numbers and distribution and was recently identified in Scandinavian countries. CWD is the only prion disease occurring both in wild and farmed animals, which, together with extensive shedding of infectivity into the environment, impedes containment strategies. There is currently a strong push to develop vaccines against CWD, including ones that can be used in wildlife. The immune system does not develop a bona fide immune response against prion infection, as PrP and PrP share an identical protein primary structure, and prions seem not to represent a trigger for immune responses. This asks for alternative vaccine strategies, which focus on PrP-directed self-antibodies or exposure of disease-specific structures and epitopes. Several groups have established a proof-of-concept that such vaccine candidates can induce some levels of protective immunity in cervid and rodent models without inducing unwanted side effects. This review will highlight the most recent developments and discuss progress and challenges remaining.
Topics: Animals; Cattle; Humans; Sheep; Goals; Prion Diseases; Prions; Encephalopathy, Bovine Spongiform; Wasting Disease, Chronic; Deer; Vaccines; Goats
PubMed: 36764940
DOI: 10.1007/s00441-023-03749-7 -
Viruses Dec 2012Prion diseases or transmissible spongiform encephalopathies are a unique category of infectious protein-misfolding neurodegenerative disorders. Hypothesized to be caused... (Review)
Review
Prion diseases or transmissible spongiform encephalopathies are a unique category of infectious protein-misfolding neurodegenerative disorders. Hypothesized to be caused by misfolding of the cellular prion protein these disorders possess an infectious quality that thrives in immune-competent hosts. While much has been discovered about the routing and critical components involved in the peripheral pathogenesis of these agents there are still many aspects to be discovered. Research into this area has been extensive as it represents a major target for therapeutic intervention within this group of diseases. The main focus of pathological damage in these diseases occurs within the central nervous system. Cells of the innate immune system have been proven to be critical players in the initial pathogenesis of prion disease, and may have a role in the pathological progression of disease. Understanding how prions interact with the host innate immune system may provide us with natural pathways and mechanisms to combat these diseases prior to their neuroinvasive stage. We present here a review of the current knowledge regarding the role of the innate immune system in prion pathogenesis.
Topics: Animals; Host-Pathogen Interactions; Humans; Immunity, Innate; Prion Diseases
PubMed: 23342365
DOI: 10.3390/v4123389 -
Antioxidants & Redox Signaling Jun 2010Imbalance of brain metal homeostasis and associated oxidative stress by redox-active metals like iron and copper is an important trigger of neurotoxicity in several... (Review)
Review
Imbalance of brain metal homeostasis and associated oxidative stress by redox-active metals like iron and copper is an important trigger of neurotoxicity in several neurodegenerative conditions, including prion disorders. Whereas some reports attribute this to end-stage disease, others provide evidence for specific mechanisms leading to brain metal dyshomeostasis during disease progression. In prion disorders, imbalance of brain-iron homeostasis is observed before end-stage disease and worsens with disease progression, implicating iron-induced oxidative stress in disease pathogenesis. This is an unexpected observation, because the underlying cause of brain pathology in all prion disorders is PrP-scrapie (PrP(Sc)), a beta-sheet-rich conformation of a normal glycoprotein, the prion protein (PrP(C)). Whether brain-iron dyshomeostasis occurs because of gain of toxic function by PrP(Sc) or loss of normal function of PrP(C) remains unclear. In this review, we summarize available evidence suggesting the involvement of oxidative stress in prion-disease pathogenesis. Subsequently, we review the biology of PrP(C) to highlight its possible role in maintaining brain metal homeostasis during health and the contribution of PrP(Sc) in inducing brain metal imbalance with disease progression. Finally, we discuss possible therapeutic avenues directed at restoring brain metal homeostasis and alleviating metal-induced oxidative stress in prion disorders.
Topics: Animals; Humans; Oxidation-Reduction; Prion Diseases; Prions
PubMed: 19803746
DOI: 10.1089/ars.2009.2628 -
Biochimica Et Biophysica Acta Dec 2008Prion diseases are fatal neurodegenerative disorders that include Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy in animals. They are unique in... (Review)
Review
Prion diseases are fatal neurodegenerative disorders that include Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy in animals. They are unique in terms of their biology because they are caused by the conformational re-arrangement of a normal host-encoded prion protein, PrPC, to an abnormal infectious isoform, PrPSc. Currently the precise mechanism behind prion-mediated neurodegeneration remains unclear. It is hypothesised than an unknown toxic gain of function of PrPSc, or an intermediate oligomeric form, underlies neuronal death. Increasing evidence suggests a role for the ubiquitin proteasome system (UPS) in prion disease. Both wild-type PrPC and disease-associated PrP isoforms accumulate in cells after proteasome inhibition leading to increased cell death, and abnormal beta-sheet-rich PrP isoforms have been shown to inhibit the catalytic activity of the proteasome. Here we review potential interactions between prions and the proteasome outlining how the UPS may be implicated in prion-mediated neurodegeneration.
Topics: Animals; Humans; Prion Diseases; Prions; Proteasome Endopeptidase Complex
PubMed: 18644436
DOI: 10.1016/j.bbadis.2008.06.011 -
Bio Systems Dec 2021Prions or PrP (prion protein, Scrapie isoform) are proteins with an aberrant three-dimensional conformation that present the ability to alter the three-dimensional...
Prions or PrP (prion protein, Scrapie isoform) are proteins with an aberrant three-dimensional conformation that present the ability to alter the three-dimensional structure of natively folded PrP (prion protein, cellular isoform) inducing its abnormal folding, giving raise to neurological diseases known as Transmissible spongiforms encephalopathies (TSEs) or prion diseases. In this work, through a biosemiotic study, we will analyze the molecular code of meanings that are known in the molecular pathway of PrP and how it is altered in prion diseases. This biosemiotic code presents a socio-semiotic correlate in organisms that could be unraveled with the ultimate goal of understanding the code of signs that mediates the process. Finally, we will study recent works that indicate possible relationships in the code between prion proteins and other proteins such as the tau protein and alpha-synuclein to evaluate if it is possible that there is a semiotic expansion of the PrP code and prion diseases in the meaning recently expounded by Prusiner, winner of the Nobel Prize for describing these unusual pathological processes.
Topics: Animals; Genetic Code; Humans; Prion Diseases; Prion Proteins; Proteostasis Deficiencies
PubMed: 34517077
DOI: 10.1016/j.biosystems.2021.104542