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Science Advances Nov 2023Prion diseases are characterized by prion protein (PrP) transmissible aggregation and neurodegeneration, which has been linked to oxidative stress. The physiological...
Prion diseases are characterized by prion protein (PrP) transmissible aggregation and neurodegeneration, which has been linked to oxidative stress. The physiological function of PrP seems related to sequestering of redox-active Cu, and Cu dyshomeostasis is observed in prion disease brain. It is unclear whether Cu contributes to PrP aggregation, recently shown to be mediated by PrP condensation. This study indicates that Cu promotes PrP condensation in live cells at the cell surface and in vitro through copartitioning. Molecularly, Cu inhibited PrP β-structure and hydrophobic residues exposure. Oxidation, induced by HO, triggered liquid-to-solid transition of PrP:Cu condensates and promoted amyloid-like PrP aggregation. In cells, overexpression of PrP initially protected against Cu cytotoxicity but led to PrP aggregation upon extended copper exposure. Our data suggest that PrP condensates function as a buffer for copper that prevents copper toxicity but can transition into PrP aggregation at prolonged oxidative stress.
Topics: Prion Proteins; Copper; Hydrogen Peroxide; Prions
PubMed: 37922348
DOI: 10.1126/sciadv.adi7347 -
Clinical Microbiology Reviews Jul 2016Since the term protein was first coined in 1838 and protein was discovered to be the essential component of fibrin and albumin, all cellular proteins were presumed to... (Review)
Review
Since the term protein was first coined in 1838 and protein was discovered to be the essential component of fibrin and albumin, all cellular proteins were presumed to play beneficial roles in plants and mammals. However, in 1967, Griffith proposed that proteins could be infectious pathogens and postulated their involvement in scrapie, a universally fatal transmissible spongiform encephalopathy in goats and sheep. Nevertheless, this novel hypothesis had not been evidenced until 1982, when Prusiner and coworkers purified infectious particles from scrapie-infected hamster brains and demonstrated that they consisted of a specific protein that he called a "prion." Unprecedentedly, the infectious prion pathogen is actually derived from its endogenous cellular form in the central nervous system. Unlike other infectious agents, such as bacteria, viruses, and fungi, prions do not contain genetic materials such as DNA or RNA. The unique traits and genetic information of prions are believed to be encoded within the conformational structure and posttranslational modifications of the proteins. Remarkably, prion-like behavior has been recently observed in other cellular proteins-not only in pathogenic roles but also serving physiological functions. The significance of these fascinating developments in prion biology is far beyond the scope of a single cellular protein and its related disease.
Topics: Animals; Humans; Prion Proteins; Prions
PubMed: 27226089
DOI: 10.1128/CMR.00046-15 -
Current Opinion in Structural Biology Feb 2009Transmissible spongiform encephalopathies (TSEs or prion diseases) are a rare group of invariably fatal neurodegenerative disorders that affect humans and other mammals.... (Review)
Review
Transmissible spongiform encephalopathies (TSEs or prion diseases) are a rare group of invariably fatal neurodegenerative disorders that affect humans and other mammals. TSEs are protein misfolding diseases that involve the accumulation of an abnormally aggregated form of the normal host prion protein (PrP). They are unique among protein misfolding disorders in that they are transmissible and have different strains of infectious agents that are associated with unique phenotypes in vivo. A wealth of biological and biophysical evidence now suggests that the molecular basis for prion diseases may be encoded by protein conformation. The purpose of this review is to provide an overview of the existing structural information for PrP within the context of what is known about the biology of prion disease.
Topics: Amino Acid Sequence; Amyloid; Animals; Humans; Models, Molecular; Prion Diseases; Prions; Protein Folding
PubMed: 19157856
DOI: 10.1016/j.sbi.2008.12.007 -
Progress in Molecular Biology and... 2017The production of transgenic mice expressing different forms of the prion protein (PrP) or devoid of PrP has enabled researchers to study the role of PrP in the... (Review)
Review
The production of transgenic mice expressing different forms of the prion protein (PrP) or devoid of PrP has enabled researchers to study the role of PrP in the infectious process of a prion disease and its normal function in the healthy individual. A wide range of transgenic models have been produced ranging from PrP null mice, normal expression levels to overexpression models, models expressing different species of the Prnp gene and different mutations and polymorphisms within the gene. Using this range of transgenic models has allowed us to define the influence of PrP expression on disease susceptibility and transmission, assess zoonotic potential, define strains of human prion diseases, elucidate the function of PrP, and start to unravel the mechanisms involved in chronic neurodegeneration. This chapter focuses mainly on the use of the gene targeted transgenic models and summarizes the ways in which they have allowed us to study the role of PrP in prion disease and the insights they have provided into the mechanisms of neurodegenerative diseases.
Topics: Animals; Disease Susceptibility; Gene Targeting; Mice, Transgenic; Models, Animal; Prion Diseases; Prions; Research
PubMed: 28838660
DOI: 10.1016/bs.pmbts.2017.06.008 -
Prion 2010Prion diseases range from being highly infectious, for example scrapie and CWD, which show facile transmission between susceptible individuals, to showing negligible... (Review)
Review
Prion diseases range from being highly infectious, for example scrapie and CWD, which show facile transmission between susceptible individuals, to showing negligible horizontal transmission, such as BSE and CJD, which are spread via food or iatrogenically, respectively. Scrapie and CWD display considerable in vivo dissemination, with PrP(Sc) and infectivity being found in a range of peripheral tissues. This in vivo dissemination appears to facilitate the recently reported excretion of prion through multiple routes such as from skin, feces, urine, milk, nasal secretions, saliva and placenta. Furthermore, excreted scrapie and CWD agent is detected within environmental samples such as water and on the surfaces of inanimate objects. The cycle of "uptake of prion from the environment--widespread in vivo prion dissemination--prion excretion--prion persistence in the environment" is likely to explain the facile transmission and maintenance of these diseases within wild and farmed populations over many years.
Topics: Animals; Environment; Feces; Humans; PrPSc Proteins; Prion Diseases; Prions; Skin
PubMed: 20948292
DOI: 10.4161/pri.4.4.13678 -
Prion 2014The universe of prion and prion-like phenomena has expanded significantly in the past several years. Here, we overview the challenges in classifying this data...
The universe of prion and prion-like phenomena has expanded significantly in the past several years. Here, we overview the challenges in classifying this data informatically, given that terms such as "prion-like", "prion-related" or "prion-forming" do not have a stable meaning in the scientific literature. We examine the spectrum of proteins that have been described in the literature as forming prions, and discuss how "prion" can have a range of meaning, with a strict definition being for demonstration of infection with in vitro-derived recombinant prions. We suggest that although prion/prion-like phenomena can largely be apportioned into a small number of broad groups dependent on the type of transmissibility evidence for them, as new phenomena are discovered in the coming years, a detailed ontological approach might be necessary that allows for subtle definition of different "flavors" of prion / prion-like phenomena.
Topics: Computational Biology; Humans; Prions
PubMed: 24549098
DOI: 10.4161/pri.27960 -
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 -
Prion 2015Yeast [PSI(+)] prion is one of the most suitable and well characterized system for the investigation of the prion phenomenon. However, until recently, the lack of data... (Review)
Review
Yeast [PSI(+)] prion is one of the most suitable and well characterized system for the investigation of the prion phenomenon. However, until recently, the lack of data on the 3D arrangement of Sup35p prion fibrils hindered progress in this area. The recent arrival in this field of new experimental techniques led to the parallel and in-register superpleated β-structure as a consensus model for Sup35p fibrils. Here, we analyzed the effect of amino acid substitutions of the Sup35 protein through the prism of this structural model. Application of a newly developed computational approach, called ArchCandy, gives us a better understanding of the effect caused by mutations on the fibril forming potential of Sup35 protein. This bioinformatics tool can be used for the design of new mutations with desired modification of prion properties. Thus, we provide examples of how today, having progress toward elucidation of the structural arrangement of Sup35p fibrils, researchers can advance more efficiently to a better understanding of prion [PSI(+)] stability and propagation.
Topics: Amino Acid Sequence; Computational Biology; Molecular Sequence Data; Mutation; Prions; Software
PubMed: 26030475
DOI: 10.1080/19336896.2015.1044186 -
Acta Neuropathologica Jul 2021Prions are novel pathogens that are composed entirely of PrP, the self-templating conformation of the host prion protein, PrP. Prion strains are operationally defined as... (Review)
Review
Prions are novel pathogens that are composed entirely of PrP, the self-templating conformation of the host prion protein, PrP. Prion strains are operationally defined as a heritable phenotype of disease that are encoded by strain-specific conformations of PrP. The factors that influence the relative distribution of strains in a population are only beginning to be understood. For prions with an infectious etiology, environmental factors, such as strain-specific binding to surfaces and resistance to weathering, can influence which strains are available for transmission to a naïve host. Strain-specific differences in efficiency of infection by natural routes of infection can also select for prion strains. The host amino acid sequence of PrP has the greatest effect on dictating the repertoire of prion strains. The relative abundance of PrP, post-translational modifications of PrP and cellular co-factors involved in prion conversion can also provide conditions that favor the prevalence of a subset of prion strains. Additionally, prion strains can interfere with each other, influencing the emergence of a dominant strain. Overall, both environmental and host factors may influence the repertoire and distribution of strains within a population.
Topics: Animals; Biological Evolution; Environment; Humans; PrPC Proteins; PrPSc Proteins; Prion Diseases; Prions
PubMed: 33899132
DOI: 10.1007/s00401-021-02310-6 -
Acta Biochimica Et Biophysica Sinica Jun 2013The prion diseases, also known as transmissible spongiform encephalopathies, are fatal neurodegenerative disorders. According to the 'protein only' hypothesis, the key... (Review)
Review
The prion diseases, also known as transmissible spongiform encephalopathies, are fatal neurodegenerative disorders. According to the 'protein only' hypothesis, the key molecular event in the pathogenesis of prion disease is the conformational conversion of the host-derived cellular prion protein (PrP(C)) into a misfolded form (scrapie PrP, PrP(Sc)). Increasing evidence has shown that the most infectious factor is the smaller subfibrillar oligomers formed by prion proteins. Both the prion oligomer and PrP(Sc) are rich in β-sheet structure and resistant to the proteolysis of proteinase K. The prion oligomer is soluble in physiologic environments whereas PrP(Sc) is insoluble. Various prion oligomers are formed in different conditions. Prion oligomers exhibited more neurotoxicity both in vitro and in vivo than the fibrillar forms of PrP(Sc), implying that prion oligomers could be potential drug targets for attacking prion diseases. In this article, we describe recent experimental evidence regarding prion oligomers, with a special focus on prion oligomer formation and its neurotoxicity.
Topics: Animals; Biopolymers; Humans; Models, Molecular; Prions; Protein Conformation; Protein Folding
PubMed: 23557632
DOI: 10.1093/abbs/gmt037