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Progress in Molecular Biology and... 2017Transmissible spongiform encephalopathies or prion diseases are a group of fatal neurodegenerative diseases caused by unconventional infectious agents, known as prions... (Review)
Review
Transmissible spongiform encephalopathies or prion diseases are a group of fatal neurodegenerative diseases caused by unconventional infectious agents, known as prions (PrP). Prions derive from a conformational conversion of the normally folded prion protein (PrP), which acquires pathological and infectious features. Moreover, PrP is able to transmit the pathological conformation to PrP through a mechanism that is still not well understood. The generation of synthetic prions, which behave like natural prions, is of fundamental importance to study the process of PrP conversion and to assess the efficacy of therapeutic strategies to interfere with this process. Moreover, the ability of synthetic prions to induce pathology in animals confirms that the pathological properties of the prion strains are all enciphered in abnormal conformations, characterizing these infectious agents.
Topics: Animals; Humans; Prion Diseases; Prions; Protein Folding; Recombinant Proteins
PubMed: 28838659
DOI: 10.1016/bs.pmbts.2017.06.002 -
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 -
FEBS Open Bio Sep 2021Prions are self-perpetuating proteins able to switch between a soluble state and an aggregated-and-transmissible conformation. These proteinaceous entities have been... (Review)
Review
Prions are self-perpetuating proteins able to switch between a soluble state and an aggregated-and-transmissible conformation. These proteinaceous entities have been widely studied in yeast, where they are involved in hereditable phenotypic adaptations. The notion that such proteins could play functional roles and be positively selected by evolution has triggered the development of computational tools to identify prion-like proteins in different kingdoms of life. These algorithms have succeeded in screening multiple proteomes, allowing the identification of prion-like proteins in a diversity of unrelated organisms, evidencing that the prion phenomenon is well conserved among species. Interestingly enough, prion-like proteins are not only connected with the formation of functional membraneless protein-nucleic acid coacervates, but are also linked to human diseases. This review addresses state-of-the-art computational approaches to identify prion-like proteins, describes proteome-wide analysis efforts, discusses these unique proteins' functional role, and illustrates recently validated examples in different domains of life.
Topics: Algorithms; Animals; Computational Biology; Humans; Plant Proteins; Prion Proteins; Prions; Proteome; Proteomics; Reproducibility of Results
PubMed: 34057308
DOI: 10.1002/2211-5463.13213 -
The Biochemical Journal Feb 1990
Review
Topics: Animals; Cell Membrane; Detergents; Lipids; Liposomes; PrPSc Proteins; Prions; Protein Processing, Post-Translational; Solubility; Viral Proteins
PubMed: 1968741
DOI: 10.1042/bj2660001 -
Current Molecular Medicine 2017More than thirty years have passed since the discovery of the prion protein (PrP) and its causative role in transmissible spongiform encephalopathy. Since a combination... (Review)
Review
More than thirty years have passed since the discovery of the prion protein (PrP) and its causative role in transmissible spongiform encephalopathy. Since a combination of both gain- and loss-of-function mechanisms may underlay prion pathogenesis, understanding the physiological role of PrP may give important clues about disease mechanisms. Historically, the primary strategy for prion research has involved the use of human tissue, cell cultures and mammalian animal models. Nevertheless, experimental difficulties of in vivo studies and controversial observations obtained in these systems have stimulated the search for alternative animal models. PrPC is highly conserved in mammals, and PrPC-related orthologs are expressed in zebrafish, a vertebrate model organism suitable to study the mechanisms associated with human diseases. Invertebrate models, as they do not express PrPC have served to investigate the neurotoxic mechanisms of mammalian PrP. Here we overview most recent advances in the study of PrP function in normal and pathogenic conditions based on non-mammalian studies, highlighting the contribution of zebrafish, fly and worms to our current understanding of PrP biology.
Topics: Animals; Caenorhabditis elegans; Disease Models, Animal; Drosophila; Humans; Prion Diseases; Prions; Structure-Activity Relationship; Zebrafish
PubMed: 28231753
DOI: 10.2174/1566524017666170220100715 -
Current Opinion in Genetics &... Jun 1992There have been remarkably rapid advances in the understanding of prion diseases over the past year. The controversial notion that the transmissible agent may be an... (Review)
Review
There have been remarkably rapid advances in the understanding of prion diseases over the past year. The controversial notion that the transmissible agent may be an abnormal isoform of a host-encoded protein, the prion protein, is now gaining wide acceptance. The conundrum of how a disease can both be inherited as an autosomal dominant condition and also be experimentally transmissible by inoculation is beginning to make sense.
Topics: Animals; Humans; Prions; Slow Virus Diseases
PubMed: 1504620
DOI: 10.1016/s0959-437x(05)80156-x -
Uirusu Jun 2002
Review
Topics: Animals; Humans; PrPC Proteins; PrPSc Proteins; Prion Diseases; Prions
PubMed: 12227168
DOI: No ID Found -
Cell May 1998
Review
Topics: Animals; Gene Dosage; Humans; Mice; Molecular Chaperones; PrPC Proteins; PrPSc Proteins; Prion Diseases; Prions; Protein Conformation; Transgenes
PubMed: 9590169
DOI: 10.1016/s0092-8674(00)81163-0 -
Current Alzheimer Research Dec 2008The PrP propensity to adopt different structures is tightly linked to transmissible spongiform encephalopathies (TSE) which include Creutzfeldt-Jakob disease (CJD),... (Review)
Review
The PrP propensity to adopt different structures is tightly linked to transmissible spongiform encephalopathies (TSE) which include Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scjeinker (GSS) and Kuru syndrome. In most cases, TSE is associated with the accumulation in the brain of an abnormally folded protease-resistant protein, PrP Sc or PrPres, which is derived from a cellular host-encoded protease-sensitive conformer, designated PrP C. The prion propagation in the brain is postulated to occur via a conformational change of PrP C into the amyloidogenic form PrP Sc, characterized by a high beta sheet content. The characterization of PrP SC oligomers as well as their biological activity is currently an area of active research. Indeed, PrP Sc structural diversity was proposed several years ago as a hypothesis to explain the origin of "prion strain" diversity. As prion pathologies belong to protein miss-assembly diseases, investigation of PrP conformational dynamics and, more precisely, oligomerization pathways exploration will help to achieve a better understanding of the pathological events at the molecular level.
Topics: Animals; Humans; Kinetics; Models, Molecular; Prions; Protein Conformation
PubMed: 19075584
DOI: 10.2174/156720508786898497 -
Philosophical Transactions of the Royal... Feb 2001The transmissible spongiform encephalopathies (TSEs), or prion diseases, remain mysterious neurodegenerative diseases that involve perturbations in prion protein (PrP)... (Review)
Review
The transmissible spongiform encephalopathies (TSEs), or prion diseases, remain mysterious neurodegenerative diseases that involve perturbations in prion protein (PrP) structure. This article summarizes our use of in vitro models to describe how PrP is converted to the disease-associated, protease-resistant form. These models reflect many important biological parameters of TSE diseases and have been used to identify inhibitors of the PrP conversion as lead compounds in the development of anti-TSE drugs.
Topics: Animals; Cattle; Drug Design; Humans; Prion Diseases; Prions
PubMed: 11260800
DOI: 10.1098/rstb.2000.0765