Large-scale validation of skin prion seeding activity as a biomarker for diagnosis of prion diseases

Acta Neuropathologica, Год журнала: 2024, Номер 147(1)

Опубликована: Янв. 17, 2024

Язык: Английский

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Cryo-EM structure of a natural prion: chronic wasting disease fibrils from deer

Acta Neuropathologica, Год журнала: 2024, Номер 148(1)

Опубликована: Окт. 24, 2024

Chronic wasting disease (CWD) is a widely distributed prion of cervids with implications for wildlife conservation and also human livestock health. The structures infectious prions that cause CWD other natural diseases mammalian hosts have been poorly understood. Here we report 2.8 Å resolution cryogenic electron microscopy-based structure fibrils from the brain naturally infected white-tailed deer expressing most common wild-type PrP sequence. Like recently solved rodent-adapted scrapie fibrils, our atomic model contains single stacks molecules forming parallel in-register intermolecular β-sheets intervening loops comprising major N- C-terminal lobes within fibril cross-section. However, cervid host differ markedly rodent in many features, including ~ 180° twist relative orientation lobes. This suggests mechanisms underlying apparent transmission barrier to humans should facilitate more rational approaches development vaccines therapeutics.

Язык: Английский

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Automated microscopic measurement of fibrinaloid microclots and their degradation by nattokinase, the main natto protease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 7, 2024

Abstract Nattokinase, from the Japanese fermented food natto, is a protease with fibrinolytic activity that can thus degrade conventional blood clots. In some cases, however, including in Long COVID, fibrinogen polymerise into an anomalous amyloid form to create clots are resistant normal fibrinolysis and we refer as fibrinaloid microclots. These be detected fluorogenic stain thioflavin T. We describe automated microscopic technique for quantification of microclot formation, which also allows kinetics their formation aggregation recorded. here show recombinant nattokinase effective at degrading microclots vitro . This adds otherwise largely anecdotal evidence, review, might anticipated have value part therapeutic treatments individuals COVID related disorders involve

Язык: Английский

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Convergent generation of atypical prions in knockin mouse models of genetic prion disease

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(15)

Опубликована: Июль 31, 2024

Most cases of human prion disease arise due to spontaneous misfolding WT or mutant protein, yet recapitulating this event in animal models has proven challenging. It remains unclear whether generation can occur within the mouse lifespan absence protein overexpression and how disease-causing mutations affect strain properties. To address these issues, we generated knockin mice that express misfolding-prone bank vole (BVPrP). While expressing BVPrP (I109 variant) remained free from neurological disease, a subset with (D178N E200K) causing genetic developed progressive illness. Brains spontaneously ill contained disease-specific neuropathological changes as well atypical protease-resistant BVPrP. Moreover, brain extracts D178N- E200K-mutant BVPrP-knockin exhibited seeding activity transmitted Surprisingly, properties prions appeared identical before after transmission, suggesting both guide formation similar strain. These findings imply develop bona fide diseases may share uniform initial mechanism action.

Язык: Английский

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Copper drives prion protein phase separation and modulates aggregation

Science Advances, Год журнала: 2023, Номер 9(44)

Опубликована: Ноя. 3, 2023

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 sequestering redox-active Cu 2+ , dyshomeostasis is observed in disease brain. It unclear whether contributes aggregation, recently shown be mediated condensation. This study indicates that promotes condensation live cells at the cell surface vitro through copartitioning. Molecularly, inhibited β-structure hydrophobic residues exposure. Oxidation, induced H 2 O triggered liquid-to-solid transition PrP:Cu condensates promoted amyloid-like aggregation. In cells, overexpression C initially protected against cytotoxicity but led upon extended copper Our data suggest as a buffer for prevents toxicity can into prolonged

Язык: Английский

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Are fibrinaloid microclots a cause of autoimmunity in Long Covid and other post-infection diseases?

Biochemical Journal, Год журнала: 2023, Номер 480(15), С. 1217 - 1240

Опубликована: Авг. 16, 2023

It is now well established that the blood-clotting protein fibrinogen can polymerise into an anomalous form of fibrin amyloid in character; resultant clots and microclots entrap many other molecules, stain with fluorogenic stains, are rather resistant to fibrinolysis, block up microcapillaries, implicated a variety diseases including Long COVID, have been referred as fibrinaloids. A necessary corollary this polymerisation generation novel epitopes proteins would normally be seen ‘self’, otherwise immunologically silent. The precise conformation resulting fibrinaloid (that, prions classical proteins, adopt multiple, stable conformations) must depend on existing small molecules metal ions may (and some cases known to) bound before polymerisation. Any such epitopes, however, likely lead autoantibodies. convergent phenomenology, distinct conformations seeding for initiation propagation, emerging link knowledge prions, prionoids, amyloids We here summarise evidence above reasoning, which has substantial implications our understanding genesis autoimmunity possible prevention thereof) based primary process formation.

Язык: Английский

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Early Alzheimer’s Disease with frequent neuritic plaques harbors neocortical tau seeds distinct from primary age-related tauopathy

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 21, 2025

Tau neurofibrillary tangles (NFTs) in the presence of amyloid-β (Aβ) plaques are required for diagnosis Alzheimer's Disease (AD) and closely track with cognitive impairment, yet cognitively normal aged individuals frequently exhibit NFTs arising from tau seed accumulation. This may suggest that not all species equally pathogenic raises question whether unidentified modifications augment seeding activity neurodegeneration AD. We investigated how biochemical relate to clinicopathological outcomes a cohort 38 patients Braak-matched AD neuropathologic change (ADNC) or primary age-related tauopathy (PART), 3R/4R identical filament core structure ADNC but little no Aβ deposition. comprehensively measured histologic density, using real-time quaking induced conversion (RT-QuIC) amplification assays, select post-translational (PTMs) (i.e. pT217, pS202/T205, & C-terminal epitopes) hippocampus neocortex. Even cases without overt neocortical neuropathology, substantial hippocampal occurred both PART predicted region-specific performance longitudinal decline. Notably, PTM profiles were associated neuritic plaque density differentiated Our data indicate meaningfully disease trajectory, potentially explaining more severe dysfunction observed late-stage versus PART. Abnormal, misfolded proteins found Tauopathies, suggesting pathogenic. Here, authors show modification two tauopathies.

Язык: Английский

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Limitations and Applications of Rodent Models in Tauopathy and Synucleinopathy Research

Journal of Neurochemistry, Год журнала: 2025, Номер 169(3)

Опубликована: Март 1, 2025

Rodent models that accurately recapitulate key aspects of human disease have long been fundamental to the successful development clinical interventions. This is greatly underscored in neurodegenerative field, where preclinical testing anti-prion therapeutics against rodent-adapted prions resulted small molecules effective but not prions. These findings provided critical lessons for ongoing efforts develop treatments patients with diseases caused by misfolding and accumulation proteins tau α-synuclein, or tauopathies synucleinopathies, respectively. To avoid potential pitfalls previously identified prion this review focuses on rodent currently available study α-synuclein pathogenesis, emphasizing strengths limitations each particular goal better supporting research.

Язык: Английский

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The Evolution of Experimental Rodent Models for Prion Diseases

Journal of Neurochemistry, Год журнала: 2025, Номер 169(3)

Опубликована: Март 1, 2025

ABSTRACT Prion diseases are a group of fatal, neurodegenerative that affect animals and humans. These characterized by the conformational conversion normal, host‐encoded PrP C into disease‐causing prion isoform, Sc . Significant advancements in biological, genetic, research have led to capability studying this pathogenetic process using recombinant proteins, ex vivo systems, vitro models, mammalian hosts, latter being gold standard for assaying infectivity, transmission, strain evolution. While devoid nucleic acid, prions encipher information conformation their constituent infectious with diversity altering pathogenesis, host‐range dynamics, efficacy therapeutics. To properly study properties natural develop appropriate therapeutic strategies, it is essential utilize models authentically recapitulate these agents experimental hosts. In review, we examine evolution on non‐transgenic transgenic animals, primarily focusing rodent models. We discuss successes limitations each system provide insights based recent findings novel gene‐targeted mice. image

Язык: Английский

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Breaking the Mould: How the First Structure of a Deer Prion Suggests the Framework for Interspecies Strain Diversity and Transmission Barriers

Journal of Neurochemistry, Год журнала: 2025, Номер 169(3)

Опубликована: Март 1, 2025

ABSTRACT Our Insight into the Structural Diversity of Prions Has Been Limited by Studies Focused on Rodent‐Adapted Sheep (Scrapie) Prion Strains, Until Now. In a Recent Paper (Alam et al. 2024), Caughey Research Group Presents First Structure from Naturally Occurring Chronic Wasting Disease (CWD), Offering Fresh Perspective. image

Язык: Английский

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