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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 -
European Review For Medical and... Nov 2015Prions are unprecedented infectious pathogens that are devoid of nucleic acid and cause a group of rare and invariably fatal neurodegenerative disorders, affecting... (Review)
Review
Prions are unprecedented infectious pathogens that are devoid of nucleic acid and cause a group of rare and invariably fatal neurodegenerative disorders, affecting approximately 1 person per 1 million inhabitants annually worldwide. These disorders include Creutzfeld-Jacob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), kuru, fatal insomnia (FI), and variable protease-sensitive prionopathy (VPSPr), all of which involve a conformational change of the normal cellular prion protein (PrPC) into the abnormal scrapie prion protein (PrPSc) through a posttranslational process during which PrPc acquires high β-sheet content. This structural change is accompanied by profound changes in the physicochemical properties of PrPC, rendering the molecule resistant to proteolysis. The conformational change of PrPC can occur due to either spontaneous conversion, dominant mutations in the prion protein (PRNP) gene encoding PrPC, or infection with pathogenic isoform PrPsc from exogenous sources. There is general agreement that PrPC serves as a substrate for conversion to abnormal PrPSc. This latter multiplies exponentially and aggregates in the brain, forming deposits that are associated with the neurodegenerative changes. Although the understanding of the primary causes of prion-induced neurodegeneration is still limited, propagation of PrPSc and neurotoxic signaling seem to interplay in pathogenic process of prions. Here, we review recent findings that have provided fresh insights into this process, and present an overview of incidence, causes and spectrum of related disorders.
Topics: Animals; Humans; Mutation; Prion Diseases; Prions
PubMed: 26592824
DOI: No ID Found -
Prion 2015In recent years, prion protein (PrP(C)) has been considered as a promising target molecule for cancer therapies, due its direct or indirect participation in tumor... (Review)
Review
In recent years, prion protein (PrP(C)) has been considered as a promising target molecule for cancer therapies, due its direct or indirect participation in tumor growth, metastasis, and resistance to cell death induced by chemotherapy. PrP(C) functions as a scaffold protein, forming multiprotein complexes on the plasma membrane, which elicits distinct signaling pathways involved in diverse biological phenomena and could be modulated depending on the cell type, complex composition, and organization. In addition, PrP(C) and its partners participate in self-renewal of embryonic, tissue-specific stem cells and cancer stem cells, which are suggested to be responsible for the origin, maintenance, relapse, and dissemination of tumors. Interference with protein-protein interaction has been recognized as an important therapeutic strategy in cancer; indeed, the possible interference in PrP(C) engagement with specific partners is a novel strategy. Recently, our group successfully used that approach to interfere with the interaction between PrP(C) and HSP-90/70 organizing protein (HOP, also known as stress-inducible protein 1 - STI1) to control the growth of human glioblastoma in animal models. Thus, PrP(C)-organized multicomplexes have emerged as feasible candidates for anti-tumor therapy, warranting further exploration.
Topics: Animals; Humans; Ligands; Neoplasms; Neoplastic Stem Cells; Prions; Protein Binding; Signal Transduction
PubMed: 26110608
DOI: 10.1080/19336896.2015.1027855 -
Viruses Apr 2019Yeast prions are protein-based genetic elements found in the baker's yeast , most of which are amyloid aggregates that propagate by fragmentation and spreading of small,... (Review)
Review
Yeast prions are protein-based genetic elements found in the baker's yeast , most of which are amyloid aggregates that propagate by fragmentation and spreading of small, self-templating pieces called propagons. Fragmentation is carried out by molecular chaperones, specifically Hsp104, Hsp70, and Hsp40. Like other amyloid-forming proteins, amyloid-based yeast prions exhibit structural polymorphisms, termed "strains" in mammalian systems and "variants" in yeast, which demonstrate diverse phenotypes and chaperone requirements for propagation. Here, the known differential interactions between chaperone proteins and yeast prion variants are reviewed, specifically those of the yeast prions [], []/[], and [3]. For these prions, differences in variant-chaperone interactions (where known) with Hsp104, Hsp70s, Hsp40s, Sse1, and Hsp90 are summarized, as well as some interactions with chaperones of other species expressed in yeast. As amyloid structural differences greatly impact chaperone interactions, understanding and accounting for these variations may be crucial to the study of chaperones and both prion and non-prion amyloids.
Topics: Amyloid; Amyloidogenic Proteins; Models, Biological; Molecular Chaperones; Prions; Protein Interaction Domains and Motifs; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 30995727
DOI: 10.3390/v11040349 -
Annual Review of Neuroscience Jul 2015The prion paradigm has emerged as a unifying molecular principle for the pathogenesis of many age-related neurodegenerative diseases. This paradigm holds that a... (Review)
Review
The prion paradigm has emerged as a unifying molecular principle for the pathogenesis of many age-related neurodegenerative diseases. This paradigm holds that a fundamental cause of specific disorders is the misfolding and seeded aggregation of certain proteins. The concept arose from the discovery that devastating brain diseases called spongiform encephalopathies are transmissible to new hosts by agents consisting solely of a misfolded protein, now known as the prion protein. Accordingly, "prion" was defined as a "proteinaceous infectious particle." As the concept has expanded to include other diseases, many of which are not infectious by any conventional definition, the designation of prions as infectious agents has become problematic. We propose to define prions as "proteinaceous nucleating particles" to highlight the molecular action of the agents, lessen unwarranted apprehension about the transmissibility of noninfectious proteopathies, and promote the wider acceptance of this revolutionary paradigm by the biomedical community.
Topics: Animals; Humans; Neurodegenerative Diseases; Prions
PubMed: 25840008
DOI: 10.1146/annurev-neuro-071714-033828 -
The Journal of Biological Chemistry Nov 2023Prion diseases are a group of transmissible neurodegenerative diseases primarily caused by the conformational conversion of prion protein (PrP) from α-helix-dominant...
Prion diseases are a group of transmissible neurodegenerative diseases primarily caused by the conformational conversion of prion protein (PrP) from α-helix-dominant cellular prion protein (PrP) to β-sheet-rich pathological aggregated form of PrP in many mammalian species. Dogs exhibit resistance to prion diseases, but the mechanism behind the phenomenon remains poorly understood. Compared with human PrP and mouse PrP, dog PrP has two unique amino acid residues, Arg177 and Asp159. Because PrP contains a low-complexity and intrinsically disordered region in its N-terminal domain, it undergoes liquid-liquid phase separation (LLPS) in vitro and forms protein condensates. However, little is known about whether these two unique residues modulate the formation of PrP condensates. Here, using confocal microscopy, fluorescence recovery after photobleaching assays, thioflavin T binding assays, and transmission electron microscopy, we report that Arg177 and Asp159 from the dog PrP slow the LLPS of full-length human PrP, shifting the equilibrium phase boundary to higher protein concentrations and inhibit amyloid formation of the human protein. In sharp contrast, His177 and Asn159 from the human PrP enhance the LLPS of full-length dog PrP, shifting the equilibrium phase boundary to lower protein concentrations, and promote fibril formation of the canid protein. Collectively, these results demonstrate how LLPS and amyloid formation of PrP are inhibited by a single residue Arg177 or Asp159 associated with prion disease resistance, and how LLPS and fibril formation of PrP are promoted by a single residue His177 or Asn159. Therefore, Arg177/His177 and Asp159/Asn159 are key residues in modulating PrP liquid-phase condensation.
Topics: Mice; Dogs; Humans; Animals; Prion Proteins; Prions; Amyloid; Amyloidogenic Proteins; Prion Diseases; Mammals
PubMed: 37805139
DOI: 10.1016/j.jbc.2023.105329 -
Frontiers in Cellular and Infection... 2024Abnormal behavior of α-synuclein and prion proteins is the hallmark of Parkinson's disease (PD) and prion illnesses, respectively, being complex neurological disorders.... (Review)
Review
Abnormal behavior of α-synuclein and prion proteins is the hallmark of Parkinson's disease (PD) and prion illnesses, respectively, being complex neurological disorders. A primary cause of protein aggregation, brain injury, and cognitive loss in prion illnesses is the misfolding of normal cellular prion proteins (PrP) into an infectious form (PrP). Aggregation of α-synuclein causes disruptions in cellular processes in Parkinson's disease (PD), leading to loss of dopamine-producing neurons and motor symptoms. Alteration in the composition or activity of gut microbes may weaken the intestinal barrier and make it possible for prions to go from the gut to the brain. The gut-brain axis is linked to neuroinflammation; the metabolites produced by the gut microbiota affect the aggregation of α-synuclein, regulate inflammation and immunological responses, and may influence the course of the disease and neurotoxicity of proteins, even if their primary targets are distinct proteins. This thorough analysis explores the complex interactions that exist between the gut microbiota and neurodegenerative illnesses, particularly Parkinson's disease (PD) and prion disorders. The involvement of the gut microbiota, a complex collection of bacteria, archaea, fungi, viruses etc., in various neurological illnesses is becoming increasingly recognized. The gut microbiome influences neuroinflammation, neurotransmitter synthesis, mitochondrial function, and intestinal barrier integrity through the gut-brain axis, which contributes to the development and progression of disease. The review delves into the molecular mechanisms that underlie these relationships, emphasizing the effects of microbial metabolites such as bacterial lipopolysaccharides (LPS), and short-chain fatty acids (SCFAs) in regulating brain functioning. Additionally, it looks at how environmental influences and dietary decisions affect the gut microbiome and whether they could be risk factors for neurodegenerative illnesses. This study concludes by highlighting the critical role that the gut microbiota plays in the development of Parkinson's disease (PD) and prion disease. It also provides a promising direction for future research and possible treatment approaches. People afflicted by these difficult ailments may find hope in new preventive and therapeutic approaches if the role of the gut microbiota in these diseases is better understood.
Topics: Humans; alpha-Synuclein; Dysbiosis; Gastrointestinal Microbiome; Neuroinflammatory Diseases; Parkinson Disease; Prion Proteins; Prions
PubMed: 38435303
DOI: 10.3389/fcimb.2024.1348279 -
Viruses Aug 2022Generating a prion with exogenously produced recombinant prion protein is widely accepted as the ultimate proof of the prion hypothesis. Over the years, a plethora of... (Review)
Review
Generating a prion with exogenously produced recombinant prion protein is widely accepted as the ultimate proof of the prion hypothesis. Over the years, a plethora of misfolded recPrP conformers have been generated, but despite their seeding capability, many of them have failed to elicit a fatal neurodegenerative disorder in wild-type animals like a naturally occurring prion. The application of the protein misfolding cyclic amplification technique and the inclusion of non-protein cofactors in the reaction mixture have led to the generation of authentic recombinant prions that fully recapitulate the characteristics of native prions. Together, these studies reveal that recPrP can stably exist in a variety of misfolded conformations and when inoculated into wild-type animals, misfolded recPrP conformers cause a wide range of outcomes, from being completely innocuous to lethal. Since all these recPrP conformers possess seeding capabilities, these results clearly suggest that seeding activity alone is not equivalent to prion activity. Instead, authentic prions are those PrP conformers that are not only heritable (the ability to seed the conversion of normal PrP) but also pathogenic (the ability to cause fatal neurodegeneration). The knowledge gained from the studies of the recombinant prion is important for us to understand the pathogenesis of prion disease and the roles of misfolded proteins in other neurodegenerative disorders.
Topics: Animals; Mammals; Neurodegenerative Diseases; Prion Diseases; Prion Proteins; Prions; Protein Folding; Recombinant Proteins
PubMed: 36146746
DOI: 10.3390/v14091940 -
Cold Spring Harbor Perspectives in... May 2017Prions are self-propagating protein conformations that are traditionally regarded as agents of neurodegenerative disease in animals. However, it has become evident that... (Review)
Review
Prions are self-propagating protein conformations that are traditionally regarded as agents of neurodegenerative disease in animals. However, it has become evident that prion-like aggregation of endogenous proteins can also occur under normal physiological conditions (e.g., during memory storage or activation of the immune response). In this review, we focus on the functional prion-related protein TIA-1, an RNA-binding protein that is involved in multiple aspects of RNA metabolism but is best understood in terms of its role in stress granule assembly during the cellular stress response. We propose that stress granule formation provides a useful conceptual framework with which to address the positive role of TIA-1 prion-like aggregation. Elucidating the function of TIA-1 prion-like aggregation will advance our understanding of how prion-based molecular switches are used in normal physiological settings.
Topics: Animals; Humans; Memory; Neurodegenerative Diseases; Prions; T-Cell Intracellular Antigen-1
PubMed: 28003185
DOI: 10.1101/cshperspect.a030718 -
Scientific Reports May 2022Prion diseases are fatal neurodegenerative conditions that affect humans and animals. Rapid and accurate sequencing of the prion gene PRNP is paramount to human prion...
Prion diseases are fatal neurodegenerative conditions that affect humans and animals. Rapid and accurate sequencing of the prion gene PRNP is paramount to human prion disease diagnosis and for animal surveillance programmes. Current methods for PRNP genotyping involve sequencing of small fragments within the protein-coding region. The contribution of variants in the non-coding regions of PRNP including large structural changes is poorly understood. Here, we used long-range PCR and Nanopore sequencing to sequence the full length of PRNP, including its regulatory region, in 25 samples from blood and brain of individuals with inherited or sporadic prion diseases. Nanopore sequencing detected the same variants as identified by Sanger sequencing, including repeat expansions/deletions. Nanopore identified additional single-nucleotide variants in the non-coding regions of PRNP, but no novel structural variants were discovered. Finally, we explored somatic mosaicism of PRNP's octapeptide repeat region, which is a hypothetical cause of sporadic prion disease. While we found changes consistent with somatic mutations, we demonstrate that they may have been generated by the PCR. Our study illustrates the accuracy of Nanopore sequencing for rapid and field prion disease diagnosis and highlights the need for single-molecule sequencing methods for the detection of somatic mutations.
Topics: Animals; Mutation; Nanopore Sequencing; Prion Diseases; Prion Proteins; Prions
PubMed: 35585119
DOI: 10.1038/s41598-022-12130-7