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Prion Dec 2020Prion diseases are characterized by the self-templated misfolding of the cellular prion protein (PrP) into infectious aggregates (PrP). The detailed molecular basis of... (Review)
Review
Prion diseases are characterized by the self-templated misfolding of the cellular prion protein (PrP) into infectious aggregates (PrP). The detailed molecular basis of the misfolding and aggregation of PrP remains incompletely understood. It is believed that the transient misfolding of PrP into partially structured intermediates precedes the formation of insoluble protein aggregates and is a critical component of the prion misfolding pathway. A number of environmental factors have been shown to induce the destabilization of PrP and promote its initial misfolding. Recently, oxidative stress and reactive oxygen species (ROS) have emerged as one possible mechanism by which the destabilization of PrP can be induced under physiological conditions. Methionine residues are uniquely vulnerable to oxidation by ROS and the formation of methionine sulfoxides leads to the misfolding and subsequent aggregation of PrP. Here, we provide a review of the evidence for the oxidation of methionine residues in PrP and its potential role in the formation of pathogenic prion aggregates.
Topics: Amino Acid Sequence; Animals; Humans; Methionine; Oxidation-Reduction; Oxidative Stress; PrPSc Proteins; Prion Diseases; Prion Proteins
PubMed: 32744136
DOI: 10.1080/19336896.2020.1796898 -
The Journal of Biological Chemistry Aug 2022The structures of prion protein (PrP)-based mammalian prions have long been elusive. However, cryo-EM has begun to reveal the near-atomic resolution structures of fully... (Review)
Review
The structures of prion protein (PrP)-based mammalian prions have long been elusive. However, cryo-EM has begun to reveal the near-atomic resolution structures of fully infectious ex vivo mammalian prion fibrils as well as relatively innocuous synthetic PrP amyloids. Comparisons of these various types of PrP fibrils are now providing initial clues to structural features that correlate with pathogenicity. As first indicated by electron paramagnetic resonance and solid-state NMR studies of synthetic amyloids, all sufficiently resolved PrP fibrils of any sort (n > 10) have parallel in-register intermolecular β-stack architectures. Cryo-EM has shown that infectious brain-derived prion fibrils of the rodent-adapted 263K and RML scrapie strains have much larger ordered cores than the synthetic fibrils. These bona fide prion strains share major structural motifs, but the conformational details and the overall shape of the fibril cross sections differ markedly. Such motif variations, as well as differences in sequence within the ordered polypeptide cores, likely contribute to strain-dependent templating. When present, N-linked glycans and glycophosphatidylinositol (GPI) anchors project outward from the fibril surface. For the mouse RML strain, these posttranslational modifications have little effect on the core structure. In the GPI-anchored prion structures, a linear array of GPI anchors along the twisting fibril axis appears likely to bind membranes in vivo, and as such, may account for pathognomonic membrane distortions seen in prion diseases. In this review, we focus on these infectious prion structures and their implications regarding prion replication mechanisms, strains, transmission barriers, and molecular pathogenesis.
Topics: Amyloid; Animals; Biology; Mammals; Mice; Prion Diseases; Prion Proteins; Prions; Scrapie; Sheep
PubMed: 35752366
DOI: 10.1016/j.jbc.2022.102181 -
Yeast (Chichester, England) Aug 2019Sup35p is an essential protein in yeast that functions in complex with Sup45p for efficient translation termination. Although some may argue that this function is the... (Review)
Review
Sup35p is an essential protein in yeast that functions in complex with Sup45p for efficient translation termination. Although some may argue that this function is the only important attribute of Sup35p, there are two additional known facets of Sup35p's biology that may provide equally important functions for yeast; both of which involve various strategies for coping with stress. Recently, the N-terminal and middle regions (NM) of Sup35p, which are not required for translation termination function, have been found to provide stress-sensing abilities and facilitate the phase separation of Sup35p into biomolecular condensates in response to transient stress. Interestingly, the same NM domain is also required for Sup35p to misfold and enter into aggregates associated with the [PSI ] prion. Here, we review these three different states or "faces" of Sup35p. For each, we compare the functionality and necessity of different Sup35p domains, including the role these domains play in facilitating interactions with important protein partners, and discuss the potential ramifications that each state affords yeast cells under varying environmental conditions.
Topics: Adaptation, Physiological; Models, Biological; Peptide Termination Factors; Phase Transition; Prions; Protein Biosynthesis; Protein Domains; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 30963611
DOI: 10.1002/yea.3392 -
Brain : a Journal of Neurology Jun 2023This scientific commentary refers to ‘Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease’ by Mok...
This scientific commentary refers to ‘Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease’ by Mok (https://doi.org/10.1093/brain/awad101).
Topics: Humans; Prions; Prion Diseases
PubMed: 37161596
DOI: 10.1093/brain/awad143 -
Journal of Enzyme Inhibition and... Dec 2023Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrP) that forms insoluble...
Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrP) that forms insoluble amyloids to impair brain function. PrP interacts with the non-pathogenic, cellular prion protein (PrP) and facilitates conversion into a nascent misfolded isoform. Several small molecules have been reported to inhibit the aggregation of PrP but no pharmacological intervention was well established thus far. We, here, report that acylthiosemicarbazides inhibit the prion aggregation. Compounds and showed almost perfect inhibition (EC = 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 = 0.9 and 2.8 µM, respectively). These compounds also disaggregated pre-existing aggregates and one of them decreased the level of PrP 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.
Topics: Humans; Prions; Prion Proteins; Brain; Prion Diseases; Cells, Cultured
PubMed: 36950944
DOI: 10.1080/14756366.2023.2191164 -
Nature Communications Aug 2023RIG-I-MAVS signaling pathway plays a crucial role in defending against pathogen infection and maintaining immune balance. Upon detecting viral RNA, RIG-I triggers the...
RIG-I-MAVS signaling pathway plays a crucial role in defending against pathogen infection and maintaining immune balance. Upon detecting viral RNA, RIG-I triggers the formation of prion-like aggregates of the adaptor protein MAVS, which then activates the innate antiviral immune response. However, the mechanisms that regulate the aggregation of MAVS are not yet fully understood. Here, we identified WDR77 as a MAVS-associated protein, which negatively regulates MAVS aggregation. WDR77 binds to MAVS proline-rich region through its WD2-WD3-WD4 domain and inhibits the formation of prion-like filament of recombinant MAVS in vitro. In response to virus infection, WDR77 is recruited to MAVS to prevent the formation of its prion-like aggregates and thus downregulate RIG-I-MAVS signaling in cells. WDR77 deficiency significantly potentiates the induction of antiviral genes upon negative-strand RNA virus infections, and myeloid-specific Wdr77-deficient mice are more resistant to RNA virus infection. Our findings reveal that WDR77 acts as a negative regulator of the RIG-I-MAVS signaling pathway by inhibiting the prion-like aggregation of MAVS to prevent harmful inflammation.
Topics: Animals; Mice; Adaptor Proteins, Signal Transducing; Antiviral Agents; Immunity, Innate; Prions; RNA Virus Infections; Signal Transduction
PubMed: 37563140
DOI: 10.1038/s41467-023-40567-5 -
Cell and Tissue Research Apr 2023Real-time quaking-induced conversion (RT-QuIC) is a cell-free abnormal form of prion protein (PrP) amplification method using recombinant prion protein from Escherichia... (Review)
Review
Real-time quaking-induced conversion (RT-QuIC) is a cell-free abnormal form of prion protein (PrP) amplification method using recombinant prion protein from Escherichia coli that can measure prion seeding activity in samples with high sensitivity. The advantages of this method are that it is much more sensitive than Western blotting, which is usually used to detect PrP, and that prion seeding activity can be easily quantified by combining it with endpoint dilution of the sample, and that it can be amplified in most species and prion strains. A decade has passed since the development of RT-QuIC, and many studies have been reported that take advantage of its characteristics. In particular, its usefulness in the diagnosis of sporadic CJD has been clarified, and it is recommended to be one of the diagnostic criteria. Future challenges include the establishment of a method to differentiate prion strains and application of RT-QuIC to early diagnosis of prion diseases and determination of treatment efficacy.
Topics: Animals; Cattle; Prions; Prion Proteins; Creutzfeldt-Jakob Syndrome; Encephalopathy, Bovine Spongiform; Blotting, Western; Recombinant Proteins; Prion Diseases
PubMed: 35084571
DOI: 10.1007/s00441-021-03568-8 -
Emerging Topics in Life Sciences Sep 2020Prions were initially discovered in studies of scrapie, a transmissible neurodegenerative disease (ND) of sheep and goats thought to be caused by slow viruses. Once... (Review)
Review
Prions were initially discovered in studies of scrapie, a transmissible neurodegenerative disease (ND) of sheep and goats thought to be caused by slow viruses. Once scrapie was transmitted to rodents, it was discovered that the scrapie pathogen resisted inactivation by procedures that modify nucleic acids. Eventually, this novel pathogen proved to be a protein of 209 amino acids, which is encoded by a chromosomal gene. After the absence of a nucleic acid within the scrapie agent was established, the mechanism of infectivity posed a conundrum and eliminated a hypothetical virus. Subsequently, the infectious scrapie prion protein (PrPSc) enriched for β-sheet was found to be generated from the cellular prion protein (PrPC) that is predominantly α-helical. The post-translational process that features in nascent prion formation involves a templated conformational change in PrPC that results in an infectious copy of PrPSc. Thus, prions are proteins that adopt alternative conformations, which are self-propagating and found in organisms ranging from yeast to humans. Prions have been found in both Alzheimer's (AD) and Parkinson's (PD) diseases. Mutations in APP and α-synuclein genes have been shown to cause familial AD and PD. Recently, AD was found to be a double prion disorder: both Aβ and tau prions feature in this ND. Increasing evidence argues for α-synuclein prions as the cause of PD, multiple system atrophy, and Lewy body dementia.
Topics: Amyloid beta-Peptides; Animals; Humans; Mutant Proteins; Mutation; PrPSc Proteins; Prion Diseases; Prion Proteins; Prions; Protein Conformation; alpha-Synuclein; tau Proteins
PubMed: 32803268
DOI: 10.1042/ETLS20200037 -
Cell and Tissue Research Apr 2023Chronic wasting disease (CWD) is a fatal neurodegenerative prion disease of cervid species including deer, elk, moose and reindeer. The disease has shown both geographic... (Review)
Review
Chronic wasting disease (CWD) is a fatal neurodegenerative prion disease of cervid species including deer, elk, moose and reindeer. The disease has shown both geographic and species expansion since its discovery in the late 1960's and is now recognized in captive and free-ranging cervid populations in North America, Asia and Europe. The facile transmission of CWD is unique among prion diseases and has resulted in growing concern for cervid populations and human public health. The development of native cervid host models with longitudinal monitoring has revealed new insights about CWD pathogenesis and transmission dynamics. More than 20 years of experimental studies conducted in these models, using biologically relevant routes of infection, have led to better understanding of many aspect of CWD infections. This review addresses some of these insights, including: (i) the temporal intra-host trafficking of CWD prions in tissues and bodily fluids, (ii) the presence of infectivity shed in bodily excretions that may help explain the facile transmission of CWD, (iii) mother-to-offspring CWD transmission, (iv) the influence of some Prnp polymorphisms on CWD susceptibility, and (vi) continued development of vaccine strategies to mitigate CWD.
Topics: Humans; Animals; Wasting Disease, Chronic; Deer; Prions; Prion Proteins; Models, Animal
PubMed: 35113219
DOI: 10.1007/s00441-022-03590-4 -
Cells Oct 2023Prion diseases are neurodegenerative disorders that are progressive, incurable, and deadly. The prion consists of PrP, the misfolded pathogenic isoform of the cellular... (Review)
Review
Prion diseases are neurodegenerative disorders that are progressive, incurable, and deadly. The prion consists of PrP, the misfolded pathogenic isoform of the cellular prion protein (PrP). PrP is involved in a variety of physiological functions, including cellular proliferation, adhesion, differentiation, and neural development. Prion protein is expressed on the membrane surface of a variety of stem cells (SCs), where it plays an important role in the pluripotency and self-renewal matrix, as well as in SC differentiation. SCs have been found to multiply the pathogenic form of the prion protein, implying their potential as an in vitro model for prion diseases. Furthermore, due to their capability to self-renew, differentiate, immunomodulate, and regenerate tissue, SCs are prospective cell treatments in many neurodegenerative conditions, including prion diseases. Regenerative medicine has become a new revolution in disease treatment in recent years, particularly with the introduction of SC therapy. Here, we review the data demonstrating prion diseases' biology and molecular mechanism. SC biology, therapeutic potential, and its role in understanding prion disease mechanisms are highlighted. Moreover, we summarize preclinical studies that use SCs in prion diseases.
Topics: Humans; Prion Proteins; Prion Diseases; Prions; Neurodegenerative Diseases; Stem Cells
PubMed: 37830627
DOI: 10.3390/cells12192413