A single protective polymorphism in the prion protein blocks cross‐species prion replication in cultured cells DOI

Hamza Arshad,

Zeel Patel,

Genki Amano

et al.

Journal of Neurochemistry, Journal Year: 2022, Volume and Issue: 165(2), P. 230 - 245

Published: Dec. 13, 2022

The bank vole (BV) prion protein (PrP) can function as a universal acceptor of prions. However, the molecular details BVPrP's promiscuity for replicating diverse range strains remain obscure. To develop cultured cell paradigm capable interrogating unique properties BVPrP, we generated monoclonal lines CAD5 cells lacking endogenous PrP but stably expressing either hamster (Ha), mouse (Mo), or BVPrP (M109 I109 polymorphic variants) and then challenged them with various Cells were susceptible to both prions, whereas MoPrP HaPrP could only be infected species-matched Propagation prions in resulted strain adaptation several instances, evidenced by alterations conformational stability, glycosylation, susceptibility anti-prion small molecules, inability BVPrP-adapted infect MoPrP. Interestingly, containing G127V gene variant, identified individuals resistant kuru, unable become Moreover, variant impeded spontaneous aggregation recombinant BVPrP. These results demonstrate that facilitate cross-species replication single amino acid change override prion-permissive nature This cellular will useful dissecting features allow it acceptor.

Language: Английский

Human prion diseases and the prion protein – what is the current state of knowledge? DOI Creative Commons

Reinhold Nafe,

Christophe Arendt, Elke Hattingen

et al.

Translational Neuroscience, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 1, 2023

Abstract Prion diseases and the prion protein are only partially understood so far in many aspects. This explains continued research on this topic, calling for an overview current state of knowledge. The main objective present review article is to provide a comprehensive up-to-date presentation all major features human bridging gap between basic clinical Starting with protein, insights concerning its physiological functions process pathological conversion will be highlighted. Diagnostic, molecular, aspects discussed, including information rare like prion-associated amyloidoses Huntington disease-like 1, as well question about potential threat due transmission prions from other species such chronic wasting disease. Finally, recent attempts develop future therapeutic strategies addressed.

Language: Английский

Citations

11
How is the Amyloid Fold Built? Polymorphism and the Microscopic Mechanisms of Fibril Assembly DOI Creative Commons
Liam D. Aubrey, Sheena E. Radford

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169008 - 169008

Published: Feb. 1, 2025

Language: Английский

Citations

0
Limitations and Applications of Rodent Models in Tauopathy and Synucleinopathy Research DOI Creative Commons

Emma Szegvari,

Sara A. M. Holec, Amanda L. Woerman

et al.

Journal of Neurochemistry, Journal Year: 2025, Volume and Issue: 169(3)

Published: March 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.

Language: Английский

Citations

0
The Evolution of Experimental Rodent Models for Prion Diseases DOI
Joseph DeFranco, Glenn C. Telling

Journal of Neurochemistry, Journal Year: 2025, Volume and Issue: 169(3)

Published: March 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

Language: Английский

Citations

0
Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis DOI Creative Commons
Binh A. Nguyen, Virender Singh, Shumaila Afrin

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 9, 2024

Abstract ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This is facilitated by mutations ATTRv amyloidosis, or aging ATTRwt amyloidosis. exhibits extreme phenotypic variability, whereas presentation consistent predictable. Previously, we found an unprecedented structural variability cardiac polyneuropathic ATTRv-I84S patients. In contrast, five genotypically-different patients with cardiomyopathy mixed phenotypes are structurally homogeneous. To understand fibril structure’s impact on phenotype, it necessary to study multiple sharing genotype phenotype. Here show cryo-electron microscopy structures extracted four cardiomyopathic Our confirms they share identical conformations minimal their homogenous clinical presentation. contributes understanding biopathology calls for further studies. One-Sentence Summary: Wild-type

Language: Английский

Citations

3
Effect of host and strain factors on α-synuclein prion pathogenesis DOI
Amanda L. Woerman, Jason C. Bartz

Trends in Neurosciences, Journal Year: 2024, Volume and Issue: 47(7), P. 538 - 550

Published: May 27, 2024

Language: Английский

Citations

3
Cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions DOI Creative Commons
Miguel A. Pérez‐Castro, Hasier Eraña, Enríc Vidal

et al.

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(1), P. e1012890 - e1012890

Published: Jan. 22, 2025

Prion diseases, particularly sporadic cases, pose a challenge due to their complex nature and heterogeneity. The underlying mechanism of the spontaneous conversion from PrP C Sc , hallmark prion remains elusive. To shed light on this process involvement cofactors, we have developed an in vitro system that faithfully mimics misfolding using minimal components. By employing PMSA methodology introducing isoleucine residue at position 108 mouse PrP, successfully generated recombinant murine strains with distinct biochemical biological properties. Our study aimed explore influence polyanionic cofactor modulating strain selection infectivity de novo -generated synthetic prions. These results not only validate as robust method for generating diverse bona fide prions but also emphasize significance cofactors shaping specific conformers capable crossing species barriers. Interestingly, once these are established, our findings suggest necessary infectivity. This research provides valuable insights into propagation maintenance pathobiological features cross-species transmissible highlights intricate interplay between characteristics.

Language: Английский

Citations

0
PRNP E146G mutation inherited prion disease: distinctive clinical, pathological and fluid biomarker features DOI Creative Commons

Thomas Coysh,

Zane Jaunmuktane, Laszlo L. P. Hosszu

et al.

Journal of Neurology, Journal Year: 2025, Volume and Issue: 272(4)

Published: March 29, 2025

Language: Английский

Citations

0
Excess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid–liquid phase separation implicated in myopathy DOI Creative Commons
Jing Tao, Yanping Zeng, Bin Dai

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 8, 2023

Abstract The cellular prion protein (PrP C ) is required for skeletal muscle function. Here, we report that a higher level of PrP accumulates in the cytoplasm six myopathy patients compared to controls. inhibits cell autophagy, and blocks myoblast differentiation. selectively binds subset miRNAs during differentiation, colocalization miR-214-3p was observed with excessive . We demonstrate overexpressed cells under pathological conditions, differentiation by physically interacting miRNAs, recruits these into its phase-separated condensate living myoblasts, which turn enhances liquid–liquid phase separation , promotes aggregation PrP, results inhibition autophagy-related 5-dependent autophagy bundle formation characterized incomplete regeneration.

Language: Английский

Citations

9
Emerging Trends in Cryo-EM-based Structural Studies of Neuropathological Amyloids DOI
Suman Mishra

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 435(24), P. 168361 - 168361

Published: Nov. 8, 2023

Language: Английский

Citations

8