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

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

Transmission and Characterization of Creutzfeldt–Jakob Disease and Chronic Wasting Disease in the North American Deer Mouse

Viruses, Год журнала: 2025, Номер 17(4), С. 576 - 576

Опубликована: Апрель 16, 2025

Prion transmission into rodents is essential for understanding prion strains. However, it often limited by a “species barrier” that makes challenging and complicates the study of animal human diseases. Here, we report North American deer mice (Peromyscus maniculatus) are susceptible to infection with both sporadic Creutzfeldt–Jakob disease (sCJD) chronic wasting (CWD). Experimental sCJD CWD in resulted 100% attack rates, albeit differing incubation times, CWD-inoculated taking nearly three times longer than sCJD-inoculated succumb. We observed distinct patterns spongiform vacuolation prion-protein deposition brain, as well protein-glycosylation profiles seeding kinetics RT-QuIC each strain. Adaptation on second passage led reduced periods marked strain-specific pathology, seen predominantly cortex thalamus CWD. Notably, primary infrequent vacuoles widespread punctate deposits protein while diffuse staining remarkable were passage. indistinguishable passage; however, glycosylation immunoblot maintained. also extraneural dissemination activity infection. Overall, ability transmit this model, resulting clear differences period, biochemical properties, clinical signs, pathology kinetics, indicates model has potential use tool investigate atypical cases may indicate spillover humans.

Язык: Английский