Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases that are caused by prions and affect humans and many animal species. It is now widely accepted that the infectious ...agent that causes TSEs is PrP(Sc), an aggregated moiety of the host-derived membrane glycolipoprotein PrP(C). Although PrP(C) is encoded by the host genome, prions themselves encipher many phenotypic TSE variants, known as prion strains. Prion strains are TSE isolates that, after inoculation into distinct hosts, cause disease with consistent characteristics, such as incubation period, distinct patterns of PrP(Sc) distribution and spongiosis and relative severity of the spongiform changes in the brain. The existence of such strains poses a fascinating challenge to prion research.
Prion diseases are progressive neurodegenerative disorders affecting humans and other mammalian species. The term prion, originally put forward to propose the concept that a protein could be ...infectious, refers to PrPSc, a misfolded isoform of the cellular prion protein (PrPC) that represents the pathogenetic hallmark of these disorders. The discovery that other proteins characterized by misfolding and seeded aggregation can spread from cell to cell, similarly to PrPSc, has increased interest in prion diseases. Among neurodegenerative disorders, however, prion diseases distinguish themselves for the broader phenotypic spectrum, the fastest disease progression and the existence of infectious forms that can be transmitted through the exposure to diseased tissues via ingestion, injection or transplantation. The main clinicopathological phenotypes of human prion disease include Creutzfeldt–Jakob disease, by far the most common, fatal insomnia, variably protease‐sensitive prionopathy, and Gerstmann–Sträussler–Scheinker disease. However, clinicopathological manifestations extend even beyond those predicted by this classification. Because of their transmissibility, the phenotypic diversity of prion diseases can also be propagated into syngenic hosts as prion strains with distinct characteristics, such as incubation period, pattern of PrPSc distribution and regional severity of histopathological changes in the brain. Increasing evidence indicates that different PrPSc conformers, forming distinct ordered aggregates, encipher the phenotypic variants related to prion strains. In this review, we summarize the most recent advances concerning the histo‐molecular pathology of human prion disease focusing on the phenotypic spectrum of the disease including co‐pathologies, the characterization of prion strains by experimental transmission and their correlation with the physicochemical properties of PrPSc aggregates.
Proteins such as FUS phase separate to form liquid-like condensates that can harden into less dynamic structures. However, how these properties emerge from the collective interactions of many amino ...acids remains largely unknown. Here, we use extensive mutagenesis to identify a sequence-encoded molecular grammar underlying the driving forces of phase separation of proteins in the FUS family and test aspects of this grammar in cells. Phase separation is primarily governed by multivalent interactions among tyrosine residues from prion-like domains and arginine residues from RNA-binding domains, which are modulated by negatively charged residues. Glycine residues enhance the fluidity, whereas glutamine and serine residues promote hardening. We develop a model to show that the measured saturation concentrations of phase separation are inversely proportional to the product of the numbers of arginine and tyrosine residues. These results suggest it is possible to predict phase-separation properties based on amino acid sequences.
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•Phase separation of FUS requires both the N-terminal PLD and the C-terminal RBD•Tyrosine and arginine govern the saturation concentration of phase separation•Glycine maintains liquidity, whereas glutamine and serine promote hardening•An associative polymer model predicts the phase behavior of FUS family proteins
The phase-separation behavior of FUS family proteins can be predicted by the prevalence and position of specific amino acids.
In prion and Alzheimer's diseases, the roles played by amyloid versus nonamyloid deposits in brain damage remain unresolved. In scrapie-infected transgenic mice expressing prion protein (PrP) lacking ...the glycosylphosphatidylinositol (GPI) membrane anchor, abnormal protease-resistant PrPres was deposited as amyloid plaques, rather than the usual nonamyloid form of PrPres. Although PrPres amyloid plaques induced brain damage reminiscent of Alzheimer's disease, clinical manifestations were minimal. In contrast, combined expression of anchorless and wild-type PrP produced accelerated clinical scrapie. Thus, the PrP GPI anchor may play a role in the pathogenesis of prion diseases.
Forty-three years have passed since it was first proposed that a protein could be the sole component of the infectious agent responsible for the enigmatic prion diseases. Many discoveries have ...strongly supported the prion hypothesis, but only recently has this once heretical hypothesis been widely accepted by the scientific community. In the past 3 years, researchers have achieved the ‘Holy Grail’ demonstration that infectious material can be generated in vitro using completely defined components. These breakthroughs have proven that a misfolded protein is the active component of the infectious agent, and that propagation of the disease and its unique features depend on the self-replication of the infectious folding of the prion protein. In spite of these important discoveries, it remains unclear whether another molecule besides the misfolded prion protein might be an essential element of the infectious agent. Future research promises to reveal many more intriguing features about the rogue prions.
Synthetic Mammalian Prions Legname, Giuseppe; Baskakov, Ilia V.; Nguyen, Hoang-Oanh B. ...
Science (American Association for the Advancement of Science),
07/2004, Volume:
305, Issue:
5684
Journal Article
Peer reviewed
Recombinant mouse prion protein (recMoPrP) produced in Escherichia coli was polymerized into amyloid fibrils that represent a subset of β sheet-rich structures. Fibrils consisting of recMoPrP(89-230) ...were inoculated intracerebrally into transgenic (Tg) mice expressing MoPrP(89-231). The mice developed neurologic dysfunction between 380 and 660 days after inoculation. Brain extracts showed protease-resistant PrP by Western blotting; these extracts transmitted disease to wild-type FVB mice and Tg mice overexpressing PrP, with incubation times of 150 and 90 days, respectively. Neuropathological findings suggest that a novel prion strain was created. Our results provide compelling evidence that prions are infectious proteins.
Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrP
Sc
) that forms insoluble amyloids to impair brain ...function. PrP
Sc
interacts with the non-pathogenic, cellular prion protein (PrP
C
) and facilitates conversion into a nascent misfolded isoform. Several small molecules have been reported to inhibit the aggregation of PrP
Sc
but no pharmacological intervention was well established thus far. We, here, report that acylthiosemicarbazides inhibit the prion aggregation. Compounds 7x and 7y showed almost perfect inhibition (EC
50
= 5 µM) in prion aggregation formation assay. The activity was further confirmed by atomic force microscopy, semi-denaturing detergent agarose gel electrophoresis and real-time quaking induced conversion assay (EC
50
= 0.9 and 2.8 µM, respectively). These compounds also disaggregated pre-existing aggregates in vitro and one of them decreased the level of PrP
Sc
in cultured cells with permanent prion infection, suggesting their potential as a treatment platform. In conclusion, hydroxy-2-naphthoylthiosemicarbazides can be an excellent scaffold for the discovery of anti-prion therapeutics.
The yeast prions (infectious proteins) URE3 and PSI+ are essentially non-functional (or even toxic) amyloid forms of Ure2p and Sup35p, whose normal function is in nitrogen catabolite repression and ...translation termination, respectively. Yeast has an array of systems working in normal cells that largely block infection with prions, block most prion formation, cure most nascent prions and mitigate the toxic effects of those prions that escape the first three types of systems. Here we review recent progress in defining these anti-prion systems, how they work and how they are regulated. Polymorphisms of the prion domains partially block infection with prions. Ribosome-associated chaperones ensure proper folding of nascent proteins, thus reducing PSI+ prion formation and curing many PSI+ variants that do form. Btn2p is a sequestering protein which gathers URE3 amyloid filaments to one place in the cells so that the prion is often lost by progeny cells. Proteasome impairment produces massive overexpression of Btn2p and paralog Cur1p, resulting in URE3 curing. Inversely, increased proteasome activity, by derepression of proteasome component gene transcription or by 60S ribosomal subunit gene mutation, prevents prion curing by Btn2p or Cur1p. The nonsense-mediated decay proteins (Upf1,2,3) cure many nascent PSI+ variants by associating with Sup35p directly. Normal levels of the disaggregating chaperone Hsp104 can also cure many PSI+ prion variants. By keeping the cellular levels of certain inositol polyphosphates / pyrophosphates low, Siw14p cures certain PSI+ variants. It is hoped that exploration of the yeast innate immunity to prions will lead to discovery of similar systems in humans.
Prion diseases are a unique group of infectious chronic neurodegenerative disorders to which there are no cures. Although prion infections do not stimulate adaptive immune responses in infected ...individuals, the actions of certain immune cell populations can have a significant impact on disease pathogenesis. After infection, the targeting of peripherally-acquired prions to specific immune cells in the secondary lymphoid organs (SLO), such as the lymph nodes and spleen, is essential for the efficient transmission of disease to the brain. Once the prions reach the brain, interactions with other immune cell populations can provide either host protection or accelerate the neurodegeneration. In this review, we provide a detailed account of how factors such as inflammation, ageing and pathogen co-infection can affect prion disease pathogenesis and susceptibility. For example, we discuss how changes to the abundance, function and activation status of specific immune cell populations can affect the transmission of prion diseases by peripheral routes. We also describe how the effects of systemic inflammation on certain glial cell subsets in the brains of infected individuals can accelerate the neurodegeneration. A detailed understanding of the factors that affect prion disease transmission and pathogenesis is essential for the development of novel intervention strategies.
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