The brain interactome of a permissive prion replication substrate

Neurobiology of Disease, Год журнала: 2025, Номер unknown, С. 106802 - 106802

Опубликована: Янв. 1, 2025

Bank voles are susceptible to prion strains from many different species, yet the molecular mechanisms underlying ability of bank vole protein (BVPrP) function as a universal acceptor remain unclear. Potential differences in environments and interaction networks on cell surface brain cells may contribute BVPrP's unusual behavior. To test this hypothesis, we generated knock-in mice that express physiological levels BVPrP (M109 isoform) employed mass spectrometry compare interactomes mouse (Mo) PrP following mild vivo crosslinking tissue. Substantial overlap was observed between top interactors for MoPrP, with established PrP-interactors such neural adhesion molecules, subunits Na

Язык: Английский

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Cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions

PLoS Pathogens, Год журнала: 2025, Номер 21(1), С. e1012890 - e1012890

Опубликована: Янв. 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.

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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The molecular determinants of a universal prion acceptor

PLoS Pathogens, Год журнала: 2024, Номер 20(9), С. e1012538 - e1012538

Опубликована: Сен. 10, 2024

In prion diseases, the species barrier limits transmission of prions from one to another. However, cross-species is remarkably efficient in bank voles, and this phenomenon mediated by vole protein (BVPrP). The molecular determinants BVPrP’s ability function as a universal acceptor remain incompletely defined. Building on our finding that cultured cells expressing BVPrP can replicate both mouse hamster strains, we systematically identified key residues permit replication. We found N155 N170 BVPrP, which are absent PrP but present PrP, critical for Additionally, V112, I139, M205, also required enable replication prions. Unexpectedly, E227 S230 near C-terminus severely restrict accumulation following challenge, suggesting they may have evolved counteract inherent propensity misfold. variants with an enhanced displayed accelerated spontaneous aggregation kinetics vitro . These findings suggest unusual properties governed set amino acids misfolding

Язык: Английский

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The Brain Interactome of a Permissive Prion Replication Substrate

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

Опубликована: Авг. 20, 2024

Abstract Bank voles are susceptible to prion strains from many different species, yet the molecular mechanisms underlying ability of bank vole protein (BVPrP) function as a universal acceptor remain unclear. Potential differences in environments and interaction networks on cell surface brain cells may contribute BVPrP’s unusual behavior. To test this hypothesis, we generated knock-in mice that express physiological levels BVPrP (M109 isoform) employed mass spectrometry compare interactomes mouse (Mo) PrP following mild vivo crosslinking tissue. Substantial overlap was observed between top interactors for MoPrP, with established PrP-interactors such neural adhesion molecules, subunits Na + /K -ATPases, contactin-1 being equally present two interactomes. We conclude MoPrP brains very similar. This suggests unorthodox properties unlikely be mediated by differential interactions other proteins.

Язык: Английский

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Abnormal synaptic architecture in iPSC-derived neurons from a multi-generational family with genetic Creutzfeldt-Jakob disease

Stem Cell Reports, Год журнала: 2024, Номер unknown

Опубликована: Сен. 1, 2024

Язык: Английский

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