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Progress in Molecular Biology and... 2020Since their original identification, prions have represented enigmatic agents that defy the classical concept of genetic inheritance. For almost four decades, the... (Review)
Review
Since their original identification, prions have represented enigmatic agents that defy the classical concept of genetic inheritance. For almost four decades, the high-resolution structure of PrP, the infectious and misfolded counterpart of the cellular prion protein (PrP), has remained elusive, mostly due to technical challenges posed by its high insolubility and aggregation propensity. As a result, such a lack of information has critically hampered the search for an effective therapy against prion diseases. Nevertheless, multiple attempts to get insights into the structure of PrP have provided important experimental constraints that, despite being at limited resolution, are paving the way for the application of computer-aided technologies to model the three-dimensional architecture of prions and their templated replication mechanism. Here, we review the most relevant studies carried out so far to elucidate the conformation of infectious PrP and offer an overview of the most advanced molecular models to explain prion structure and conversion.
Topics: Animals; Humans; Models, Molecular; Prion Diseases; Prions; Protein Aggregates
PubMed: 32958233
DOI: 10.1016/bs.pmbts.2020.07.005 -
Medicina Clinica Jun 2023Prion diseases are a group of neurodegenerative diseases. The disease-causing agent is a protein (PrP), that is normally produced in the nervous system, aggregated in an... (Review)
Review
Prion diseases are a group of neurodegenerative diseases. The disease-causing agent is a protein (PrP), that is normally produced in the nervous system, aggregated in an abnormal form. The abnormal protein, known as prion (PrP), is capable of self-propagation promoting the misfolding of the normal protein (PrP). These conditions can be acquired sporadically, genetically, or infectiously either by eating meat contaminated with prions or from iatrogenic exposure. The diagnosis of these diseases is often challenging. The use of highly sensitive and specific diagnostic tools, such as MRI and RT-QuIC, may aid in the diagnosis. Neuropathological examination of brain tissue ensures a definite diagnosis. At present, no treatment significantly improves the course of prion diseases; however, an early diagnosis is of paramount importance for patient care decision planning, infection control purposes, and genetic counseling.
Topics: Humans; Creutzfeldt-Jakob Syndrome; Prion Diseases; Prions; Brain
PubMed: 37088611
DOI: 10.1016/j.medcli.2023.03.001 -
Progress in Molecular Biology and... 2020
Topics: Amyloid beta-Peptides; Animals; Humans; N-Acetylneuraminic Acid; Neurodegenerative Diseases; Prion Diseases; Prions; Protein Aggregates
PubMed: 32958243
DOI: 10.1016/S1877-1173(20)30149-6 -
Science (New York, N.Y.) Jan 2024My first encounter with prion diseases dates to 1986. As a clinical resident in neuropathology, I was tasked with performing autopsies of patients who died of mysterious...
My first encounter with prion diseases dates to 1986. As a clinical resident in neuropathology, I was tasked with performing autopsies of patients who died of mysterious brain diseases. In his early 60s, my patient had developed a form of dementia that progressed at a terrifyingly rapid pace and eventually led to his death. I sampled the patient's brain and processed it for histological examination. The microscope revealed an eerie landscape of destruction. All that was left in the patient's cortex were astrocytes and microglia, and the few remaining neurons showed extensive vacuolation of their bodies and processes. Such blazing destruction of the brain was indicative of just one diagnosis: Creutzfeldt-Jakob disease, a spongiform encephalopathy caused by enigmatic infectious agents called prions.
Topics: Humans; Cerebral Cortex; Creutzfeldt-Jakob Syndrome; Prion Diseases; Prions
PubMed: 38236962
DOI: 10.1126/science.adn9424 -
Cellular and Molecular Life Sciences :... Feb 2020Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are characterized by the aggregation of misfolded proteins, including Aβ, tau and... (Review)
Review
Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are characterized by the aggregation of misfolded proteins, including Aβ, tau and α-synuclein. It is well recognized that these misfolded proteins are able to self-propagate and spread throughout the nervous system and cause neuronal injury in a way that resembles prion disease. These disease-specific misfolded proteins demonstrate unique features, including the seeding barrier, the conformational memory effect, strain selection and strain evolution, based on the presence of various strains. However, the accurate definition of the term strain remains to be clarified. Here, a clear interpretation is proposed by a retrospective of its history in prion research and the recent progress in neurodegeneration research. Furthermore, the causes contributing to the genesis of various strains are also summarized. Deeper insight into strains helps us to understand the phenomena we observe in this field and it also enlightens us on the elusive mechanisms and management of neurodegeneration.
Topics: Amyloid beta-Peptides; Animals; Humans; Neurodegenerative Diseases; Prions; Protein Aggregation, Pathological; Protein Folding; alpha-Synuclein; tau Proteins
PubMed: 31531680
DOI: 10.1007/s00018-019-03298-9 -
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 -
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 -
Nature Chemical Biology May 2023Recent cryogenic electron microscopy (cryo-EM) studies of infectious, ex vivo, prion fibrils from hamster 263K and mouse RML prion strains revealed a similar, parallel...
Recent cryogenic electron microscopy (cryo-EM) studies of infectious, ex vivo, prion fibrils from hamster 263K and mouse RML prion strains revealed a similar, parallel in-register intermolecular β-sheet (PIRIBS) amyloid architecture. Rungs of the fibrils are composed of individual prion protein (PrP) monomers that fold to create distinct N-terminal and C-terminal lobes. However, disparity in the hamster/mouse PrP sequence precludes understanding of how divergent prion strains emerge from an identical PrP substrate. In this study, we determined the near-atomic resolution cryo-EM structure of infectious, ex vivo mouse prion fibrils from the ME7 prion strain and compared this with the RML fibril structure. This structural comparison of two biologically distinct mouse-adapted prion strains suggests defined folding subdomains of PrP rungs and the way in which they are interrelated, providing a structural definition of intra-species prion strain-specific conformations.
Topics: Mice; Animals; Prions; Protein Conformation, beta-Strand; Amyloid
PubMed: 36646960
DOI: 10.1038/s41589-022-01229-7 -
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 -
International Journal of Molecular... Jul 2023The number of yeast prions and prion-like proteins described since 1994 has grown from two to nearly twenty. If in the early years most scientists working with the... (Review)
Review
The number of yeast prions and prion-like proteins described since 1994 has grown from two to nearly twenty. If in the early years most scientists working with the classic mammalian prion, PrP, were skeptical about the possibility of using the term prion to refer to yeast cytoplasmic elements with unusual properties, it is now clear that prion-like phenomena are widespread and that yeast can serve as a convenient model for studying them. Here we give a brief overview of the yeast prions discovered so far and focus our attention to the various approaches used to identify them. The prospects for the discovery of new yeast prions are also discussed.
Topics: Animals; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Prions; Amyloid; Mammals
PubMed: 37511408
DOI: 10.3390/ijms241411651