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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 -
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 -
Viruses Mar 2019Kuru, the first human prion disease was transmitted to chimpanzees by D. Carleton Gajdusek (1923⁻2008). In this review, we summarize the history of this seminal... (Review)
Review
Kuru, the first human prion disease was transmitted to chimpanzees by D. Carleton Gajdusek (1923⁻2008). In this review, we summarize the history of this seminal discovery, its anthropological background, epidemiology, clinical picture, neuropathology, and molecular genetics. We provide descriptions of electron microscopy and confocal microscopy of kuru amyloid plaques retrieved from a paraffin-embedded block of an old kuru case, named Kupenota. The discovery of kuru opened new vistas of human medicine and was pivotal in the subsequent transmission of Creutzfeldt⁻Jakob disease, as well as the relevance that bovine spongiform encephalopathy had for transmission to humans. The transmission of kuru was one of the greatest contributions to biomedical sciences of the 20th century.
Topics: Animals; Cannibalism; History, 20th Century; Humans; Kuru; Pan troglodytes; Papua New Guinea; Prions
PubMed: 30866511
DOI: 10.3390/v11030232 -
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 -
Progress in Molecular Biology and... 2017Prion disease or transmissible spongiform encephalopathies are characterized by the presence of the abnormal form of the prion protein (PrP). The pathological and... (Review)
Review
Prion disease or transmissible spongiform encephalopathies are characterized by the presence of the abnormal form of the prion protein (PrP). The pathological and transmissible properties of PrP are enciphered in its secondary and tertiary structures. Since it's well established that different strains of prions are linked to different conformations of PrP, biochemical characterization of prions seems a preliminary but reliable approach to detect, analyze, and compare prion strains. Experimental biochemical procedures might be helpful in distinguishing PrP physicochemical properties and include resistance to proteinase K (PK) digestion, insolubility in nonionic detergents, PK-resistance under denaturing conditions and sedimentation properties in sucrose gradients. This biochemical approach has been extensively applied in human prion disorders and subsequently expanded for PrP characterization in animals. In particular, in sporadic Creutzfedlt-Jakob disease (sCJD) PrP is characterized by two main glycotypes conventionally named Type 1 and Type 2, based on the apparent gel migration at 21 and 19kDa of the PrP PK-resistant fragment. An additional PrP type was identified in sCJD characterized by an unglycosylated dominant glycoform pattern and in 2010 a variably protease-sensitive prionopathy (VPSPr) was reported showing a PrP with an electrophoretic ladder like pattern. Additionally, the presence of PrP truncated fragments completes the electrophoretic characterization of different prion strains. By two-dimensional (2D) electrophoretic analysis additional PrP pattern was identified, since this procedure provides information about the isoelectric point and the different peptides length related to PK cleavage, as well as to glycosylation extent or GPI anchor presence. We here provide and extensive review on PrP biochemical analysis in human and animal prion disorders. Further, we show that PrP glycotypes observed in CJD share similarities with PrP in bovine spongiform encephalopathy forms (BSE).
Topics: Animals; Cattle; Electrophoresis, Gel, Two-Dimensional; Glycosylphosphatidylinositols; Humans; Mutation; Peptides; Prion Diseases; Prions
PubMed: 28838671
DOI: 10.1016/bs.pmbts.2017.06.012 -
Current Opinion in Neurobiology Jun 2024The concept of 'prion-like' behavior has emerged in the study of diseases involving protein misfolding where fibrillar structures, called amyloids, self-propagate and... (Review)
Review
The concept of 'prion-like' behavior has emerged in the study of diseases involving protein misfolding where fibrillar structures, called amyloids, self-propagate and induce disease in a fashion similar to prions. From a biological standpoint, in order to be considered 'prion-like,' a protein must traverse cells and tissues and further propagate via a templated conformational change. Since 2017, cryo-electron microscopy structures from patient-derived 'prion-like' amyloids, in particular tau, have been presented and revealed structural similarities shared across amyloids. Since 2021, cryo-EM structures from prions of known infectivity have been added to the ex vivo amyloid structure family. In this review, we discuss current proposals for the 'prion-like' mechanisms of spread for tau and prion protein as well as discuss different influencers on structures of aggregates from tauopathies and prion diseases. Lastly, we discuss some of the current hypotheses for what may distinguish structures that are 'prion-like' from transmissible prion structures.
Topics: Humans; tau Proteins; Animals; Prion Proteins; Prion Diseases; Tauopathies; Prions; Amyloid
PubMed: 38489865
DOI: 10.1016/j.conb.2024.102857 -
Microbiology Spectrum Dec 2016Prions are infectious protein polymers that have been found to cause fatal diseases in mammals. Prions have also been identified in fungi (yeast and filamentous fungi),... (Review)
Review
Prions are infectious protein polymers that have been found to cause fatal diseases in mammals. Prions have also been identified in fungi (yeast and filamentous fungi), where they behave as cytoplasmic non-Mendelian genetic elements. Fungal prions correspond in most cases to fibrillary β-sheet-rich protein aggregates termed amyloids. Fungal prion models and, in particular, yeast prions were instrumental in the description of fundamental aspects of prion structure and propagation. These models established the "protein-only" nature of prions, the physical basis of strain variation, and the role of a variety of chaperones in prion propagation and amyloid aggregate handling. Yeast and fungal prions do not necessarily correspond to harmful entities but can have adaptive roles in these organisms.
Topics: Amyloid; Fungal Proteins; Fungi; Prions
PubMed: 28087950
DOI: 10.1128/microbiolspec.FUNK-0029-2016 -
Virus Research Sep 2015Transmissible spongiform encephalopaties (TSEs) are fatal neurodegenerative diseases characterized by the aggregation and accumulation of the misfolded prion protein in... (Review)
Review
Transmissible spongiform encephalopaties (TSEs) are fatal neurodegenerative diseases characterized by the aggregation and accumulation of the misfolded prion protein in the brain. Other proteins such as β-amyloid, tau or Serum Amyloid-A (SAA) seem to share with prions some aspects of their pathogenic mechanism; causing a variety of so called prion-like diseases in humans and/or animals such as Alzheimer's, Parkinson's, Huntington's, Type II diabetes mellitus or amyloidosis. The question remains whether these misfolding proteins have the ability to self-propagate and transmit in a similar manner to prions. In this review, we describe the prion and prion-like diseases affecting animals as well as the recent findings suggesting the prion-like transmissibility of certain non-prion proteins.
Topics: Animals; Cats; Cattle; Mink; Prion Diseases; Prions; Sheep
PubMed: 25444937
DOI: 10.1016/j.virusres.2014.11.026 -
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