Biology subjects

Schatzl, H.

Publications and source records attributed to Schatzl, H..

3 recordsLinked to original sources

bioRxiv2026

Distinct roles of Hsp110 proteins in regulating prion propagation

Prion diseases are fatal, transmissible neurodegenerative disorders characterized by the conformational conversion of the cellular prion protein (PrPC) into its pathogenic isoform PrPSc. Propagation of prions depends on the fragmentation of PrPSc aggregates to generate new seeds. However, the factors regulating this process remain incompletely understood. For yeast prions, Hsp104 that has no mammalian homologue, is firmly established as a disaggregase. Hsp110 has emerged as a potential mediator of protein disaggregation and aggregate remodeling in mammalian cells. Although Hsp110 proteins have been implicated in several protein misfolding disorders, their individual contributions to mammalian prion propagation have not been characterized. In this study, we examined the roles of the three Hsp110 proteins -Apg-1, Apg-2, and Hsp105- in cellular prion infection. CRISPR-generated knockout cell lines were established for each Hsp110 and evaluated for their effect on de novo prion infection. PrPSc accumulation was assessed by immunoblot across serial passages and up to 40 days, and prion seeding activity was quantified using real-time quaking-induced conversion (RT-QuIC). Loss of individual Hsp110s produced distinct effects on prion propagation. Apg-1-deficient cells exhibited strongly reduced levels of PrPSc over all passages analyzed, suggesting a role for Apg-1 in establishing persistent prion infection. Interestingly, prion seeding activity was detectable in later passages. Hsp105-deficient cells displayed reduced PrPSc levels during the early stages, indicating that Hsp105 contributes to early prion replication. In contrast, Apg-2 knockout resulted in high prion seeding activity over all passages analyzed and only slightly reduced PrPSc levels in early passages. Collectively, these findings demonstrate that Hsp110 family members perform distinct functions during early phases of prion infection and establishment of persistent infection. This work provides new insight into the role of molecular chaperones in prion biology and identifies Hsp110 proteins as potential modulators of prion replication and potentially therapeutic targets for protein misfolding diseases.

molecular biology↗

bioRxiv2025

Prion shedding is reduced by chronic wasting disease vaccination

Chronic wasting disease (CWD) is a strictly fatal and highly contagious prion disease of wild and farmed cervids currently expanding in North America. Prion diseases are caused by conversion of the cellular prion protein to its pathological isoform PrPSc. Vaccination is considered a promising strategy to contain CWD, even though prion diseases do not show classical immune responses. For CWD containment, it is important that vaccines reduce shedding of prions in excreta, a major contributor to transmission. Here, we tested the effect of vaccines on prion shedding in feces and urine by vaccinating and prion infecting knock-in mice that recapitulate CWD pathogenesis as found in cervids. Vaccination reduced or even prevented CWD shedding in feces and urine collected between 30-90% of incubation time to disease. This is the first report showing that prion shedding can be blocked in a prion disease. For CWD specifically it may reduce the environmental prion burden and break the disease transmission cycle.

neuroscience↗

bioRxiv2017

PrPSc-induced conformational changes and strain-specific structures of PrPSc revealed by Disulfide-crosslink scanning

There exist many phenotypically-varied prion strains, like viruses, despite the absence of conventional genetic material which codes the phenotypic information. As prion is composed solely of the pathological isoform (PrPSc) of prion protein (PrP), the strain-specific traits are hypothesized to be enciphered in the structural details of PrPSc. Identification of the structures of PrPSc is therefore vital for the understanding of prion biology, though they remain unidentified due to the incompatibility of PrPSc with conventional high-resolution structural analyses. Based on our previous hypothesis that the region between the first and the second -helix (H1[~]H2) and the distal region of the third helix (Ctrm) of the cellular isoform of PrP (PrPC) have important roles for efficient interactions with PrPSc, we created series of mutant PrPs with two cysteine substitutions (C;C-PrP) which were systematically designed to form an intramolecular disulfide crosslink between H1[~]H2 and Ctrm and assessed their conformational changes by prions: Specifically, a cysteine substitution in H1[~]H2 from 165 to 169 was combined with cysteine-scanning along Ctrm from 220 to 229. C;C-PrPs with the crosslinks were expressed normally with the similar glycosylation patterns and subcellular localization as the wild-type PrP albeit with varied expression levels. Interestingly, some of the C;C-PrPs converted to the protease-resistant isoforms in the N2a cells persistently infected with 22L prion strain, whereas the same mutants did not convert in the cells infected with another prion strain Fukuoka1, indicating that local structures of PrPSc in these regions vary among prion strains and contribute to prion-strain diversity. Moreover, patterns of the crosslinks of the convertible C;C-PrPs implied drastic changes in positional relations of H1[~]H2 and Ctrm in the PrPSc-induced conformational changes by 22L prion. Thus, disulfide-crosslink scanning is a useful approach for investigation of strain-specific structures of PrPSc, and would be applicable to other types of amyloids as well.

molecular biology↗