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Prion 2018Protein misfolding and aggregation into highly ordered fibrillar structures have been traditionally associated with pathological processes. Nevertheless, nature has... (Review)
Review
Protein misfolding and aggregation into highly ordered fibrillar structures have been traditionally associated with pathological processes. Nevertheless, nature has taken advantage of the particular properties of amyloids for functional purposes, like in the protection of organisms against environmental changing conditions. Over the last decades, these fibrillar structures have inspired the design of new nanomaterials with intriguing applications in biomedicine and nanotechnology such as tissue engineering, drug delivery, adhesive materials, biodegradable nanocomposites, nanowires or biosensors. Prion and prion-like proteins, which are considered a subclass of amyloids, are becoming ideal candidates for the design of new and tunable nanomaterials. In this review, we discuss the particular properties of this kind of proteins, and the current advances on the design of new materials based on prion sequences.
Topics: Amyloid; Animals; Biosensing Techniques; Drug Design; Humans; Nanomedicine; Nanostructures; Prions; Tissue Engineering
PubMed: 30196749
DOI: 10.1080/19336896.2018.1521235 -
Cold Spring Harbor Perspectives in... Sep 2016Yeast and fungal prions are infectious proteins, most being self-propagating amyloids of normally soluble proteins. Their effects range from a very mild detriment to... (Review)
Review
Yeast and fungal prions are infectious proteins, most being self-propagating amyloids of normally soluble proteins. Their effects range from a very mild detriment to lethal, with specific effects dependent on the prion protein and the specific prion variant ("prion strain"). The prion amyloids of Sup35p, Ure2p, and Rnq1p are in-register, parallel, folded β-sheets, an architecture that naturally suggests a mechanism by which a protein can template its conformation, just as DNA or RNA templates its sequence. Prion propagation is critically affected by an array of chaperone systems, most notably the Hsp104/Hsp70/Hsp40 combination, which is responsible for generating new prion seeds from old filaments. The Btn2/Cur1 antiprion system cures most [URE3] prions that develop, and the Ssb antiprion system blocks [PSI+] generation.
Topics: Amyloid; Fungal Proteins; Prions; Yeasts
PubMed: 27481532
DOI: 10.1101/cshperspect.a023531 -
Progress in Molecular Biology and... 2017Transmissible spongiform encephalopathies (TSEs) are a group of progressive, invariably fatal diseases that affect the nervous system of many mammals including humans.... (Review)
Review
Transmissible spongiform encephalopathies (TSEs) are a group of progressive, invariably fatal diseases that affect the nervous system of many mammals including humans. The key molecular event in the pathogenesis of TSEs is the conversion of the cellular prion protein PrP into a disease-associated isoform PrP. The "protein-only hypothesis" argues that PrP itself is the infectious agent. In effect, PrP can adopt several structures that represent different prion strains. The interspecies transmission of TSEs is difficult because of differences between the host and donor primary PrP sequence. However, transmission is not impossible as this occurred when bovine spongiform encephalopathy spread to humans causing variant Creutzfeldt-Jakob disease (vCJD). This event determined a need for a thorough understanding of prion replication and transmission so that we could be one step ahead of further threats for human health. This chapter focuses on these concepts and on new insights gained into prion propagation mechanisms.
Topics: Animals; Humans; Models, Biological; Polymorphism, Genetic; Prion Diseases; Prions; Species Specificity
PubMed: 28838661
DOI: 10.1016/bs.pmbts.2017.06.014 -
International Journal of Molecular... Jul 2020Infectious proteins (prions) include an array of human (mammalian) and yeast amyloid diseases in which a protein or peptide forms a linear β-sheet-rich filament, at... (Review)
Review
Infectious proteins (prions) include an array of human (mammalian) and yeast amyloid diseases in which a protein or peptide forms a linear β-sheet-rich filament, at least one functional amyloid prion, and two functional infectious proteins unrelated to amyloid. In at least eight anti-prion systems deal with pathogenic amyloid yeast prions by (1) blocking their generation (Ssb1,2, Ssz1, Zuo1), (2) curing most variants as they arise (Btn2, Cur1, Hsp104, Upf1,2,3, Siw14), and (3) limiting the pathogenicity of variants that do arise and propagate (Sis1, Lug1). Known mechanisms include facilitating proper folding of the prion protein (Ssb1,2, Ssz1, Zuo1), producing highly asymmetric segregation of prion filaments in mitosis (Btn2, Hsp104), competing with the amyloid filaments for prion protein monomers (Upf1,2,3), and regulation of levels of inositol polyphosphates (Siw14). It is hoped that the discovery of yeast anti-prion systems and elucidation of their mechanisms will facilitate finding analogous or homologous systems in humans, whose manipulation may be useful in treatment.
Topics: Amyloidogenic Proteins; Animals; Evolution, Molecular; Genes, Fungal; Genetic Variation; Humans; Molecular Chaperones; Prion Proteins; Prions; Protein Folding; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 32635197
DOI: 10.3390/ijms21134742 -
Progress in Molecular Biology and... 2017Prions are the infectious agents that cause devastating and untreatable disorders known as Transmissible Spongiform Encephalopathies (TSEs). The pathologic events and... (Review)
Review
Prions are the infectious agents that cause devastating and untreatable disorders known as Transmissible Spongiform Encephalopathies (TSEs). The pathologic events and the infectious nature of these transmissible agents are not completely understood yet. Due to the difficulties in inactivating prions, working with them requires specific recommendations and precautions. Moreover, with the advent of innovative technologies, such as the Protein Misfolding Cyclic Amplification (PMCA) and the Real Time Quaking-Induced Conversion (RT-QuIC), prions could be amplified in vitro and the infectious features of the amplified products need to be carefully assessed.
Topics: Animals; Organ Specificity; Prion Diseases; Prions; Reference Standards; Risk Assessment; Social Control, Formal
PubMed: 28838674
DOI: 10.1016/bs.pmbts.2017.06.017 -
Journal of Microbiology (Seoul, Korea) Oct 2023Prions are infectious proteins that mostly replicate in self-propagating amyloid conformations (filamentous protein polymers) and consist of structurally altered normal... (Review)
Review
Prions are infectious proteins that mostly replicate in self-propagating amyloid conformations (filamentous protein polymers) and consist of structurally altered normal soluble proteins. Prions can arise spontaneously in the cell without any clear reason and are generally considered fatal disease-causing agents that are only present in mammals. However, after the seminal discovery of two prions, [PSI+] and [URE3], in the eukaryotic model microorganism Saccharomyces cerevisiae, at least ten more prions have been discovered, and their biological and pathological effects on the host, molecular structure, and the relationship between prions and cellular components have been studied. In a filamentous fungus model, Podospora anserina, a vegetative incomparability-related [Het-s] prion that directly triggers cell death during anastomosis (hyphal fusion) was discovered. These prions in eukaryotic microbes have extended our understanding to overcome most fatal human prion/amyloid diseases. A prokaryotic microorganism (Clostridium botulinum) was reported to have a prion analog. The transcriptional regulators of C. botulinum-Rho can be converted into the self-replicating prion form ([RHO-X-C+]), which may affect global transcription. Here, we outline the major issues with prions in microbes and the lessons learned from the relatively uncovered microbial prion world.
Topics: Animals; Humans; Prions; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Amyloid; Amyloidogenic Proteins; Fungal Proteins; Mammals
PubMed: 37668956
DOI: 10.1007/s12275-023-00070-4 -
International Journal of Molecular... Sep 2020Prions are infectious proteins that self-propagate by changing from their normal folded conformation to a misfolded conformation. The misfolded conformation, which is... (Review)
Review
Prions are infectious proteins that self-propagate by changing from their normal folded conformation to a misfolded conformation. The misfolded conformation, which is typically rich in β-sheet, serves as a template to convert the prion protein into its misfolded conformation. In yeast, the misfolded prion proteins are assembled into amyloid fibers or seeds, which are constantly severed and transmitted to daughter cells. To cure prions in yeast, it is necessary to eliminate all the prion seeds. Multiple mechanisms of curing have been found including inhibiting severing of the prion seeds, gradual dissolution of the prion seeds, asymmetric segregation of the prion seeds between mother and daughter cells during cell division, and degradation of the prion seeds. These mechanisms, achieved by using different protein quality control machinery, are not mutually exclusive; depending on conditions, multiple mechanisms may work simultaneously to achieve curing. This review discusses the various methods that have been used to differentiate between these mechanisms of curing.
Topics: Heat-Shock Proteins; Peptide Termination Factors; Prions; Proteolysis; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 32906758
DOI: 10.3390/ijms21186536 -
Trends in Cell Biology Jun 2018Prion-like proteins overlap with intrinsically disordered and low-complexity sequence families. These proteins are widespread, especially among mRNA-binding proteins. A... (Review)
Review
Prion-like proteins overlap with intrinsically disordered and low-complexity sequence families. These proteins are widespread, especially among mRNA-binding proteins. A salient feature of these proteins is the ability to form protein assemblies with distinct biophysical and functional properties. While prion-like proteins are involved in myriad of cellular processes, we propose potential roles for protein assemblies in regulated protein synthesis. Since proteins are the ultimate functional output of gene expression, when, where, and how much of a particular protein is made dictates the functional state of a cell. Recent finding suggests that the prion-like proteins offer unique advantages in translation regulation and also raises questions regarding formation and regulation of protein assemblies.
Topics: Gene Expression Regulation; Humans; Prions; Protein Biosynthesis; Protein Conformation; Protein Processing, Post-Translational; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 29530524
DOI: 10.1016/j.tcb.2018.02.002 -
Cold Spring Harbor Perspectives in... Feb 2017It is now established that numerous amyloid proteins associated with neurodegenerative diseases, including tau and α-synuclein, have essential characteristics of... (Review)
Review
It is now established that numerous amyloid proteins associated with neurodegenerative diseases, including tau and α-synuclein, have essential characteristics of prions, including the ability to create transmissible cellular pathology in vivo. We have developed cellular bioassays that report on the various features of prion activity using genetic engineering and quantitative fluorescence-based detection systems. We have exploited these biosensors to measure the binding and uptake of tau seeds into cells in culture and to quantify seeding activity in brain samples. These cell models have also been used to propagate tau prion strains indefinitely in culture. In this review, we illustrate the utility of cellular biosensors to gain mechanistic insight into prion transmission and to study neurodegenerative diseases in a reductionist fashion.
Topics: Animals; Biosensing Techniques; Brain; Cell Culture Techniques; Humans; Neurodegenerative Diseases; Prion Diseases; Prions; alpha-Synuclein; tau Proteins
PubMed: 27815306
DOI: 10.1101/cshperspect.a024026 -
ACS Chemical Neuroscience Mar 2018Prion diseases are phenotypically diverse, transmissible, neurodegenerative disorders affecting both animals and humans. Misfolding of the normal prion protein (PrP)... (Review)
Review
Prion diseases are phenotypically diverse, transmissible, neurodegenerative disorders affecting both animals and humans. Misfolding of the normal prion protein (PrP) into disease-associated conformers (PrP) is considered the critical etiological event underpinning prion diseases, with such misfolded isoforms linked to both disease transmission and neurotoxicity. Although important advances in our understanding of prion biology and pathogenesis have occurred over the last 3-4 decades, many fundamental questions remain to be resolved, including consensus regarding the principal pathways subserving neuronal dysfunction, as well as detailed biophysical characterization of PrP species transmitting disease and/or directly associated with neurotoxicity. In vivo and in vitro models have been, and remain, critical to furthering our understanding across many aspects of prion disease patho-biology. Prion animal models are arguably the most authentic in vivo models of neurodegeneration that exist and have provided valuable and multifarious insights into pathogenesis; however, they are expensive and time-consuming, and it can be problematic to clearly discern evidence of direct PrP neurotoxicity in the overall context of pathogenesis. In vitro models, in contrast, generally offer greater tractability and appear more suited to assessments of direct acute neurotoxicity but have until recently been relatively simplistic, and overall there remains a relative paucity of validated, biologically relevant models with heightened reliability as far as translational insights, contributing to difficulties in redressing our knowledge gaps in prion disease pathogenesis. In this review, we provide an overview of the spectrum and methodological diversity of in vivo and in vitro models of prion acute toxicity, as well as the pathogenic insights gained from these studies.
Topics: Animals; Humans; Models, Biological; Neurons; Neurotoxicity Syndromes; PrPSc Proteins; Prion Diseases; Prions
PubMed: 29393619
DOI: 10.1021/acschemneuro.7b00517