1. Characterisation and prion transmission study in mice with genetic reduction of sporadic Creutzfeldt-Jakob disease risk gene Stx6.
- Author
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Jones E, Hill E, Linehan J, Nazari T, Caulder A, Codner GF, Hutchison M, Mackenzie M, Farmer M, Coysh T, De Oliveira MW, Al-Doujaily H, Sandberg M, Viré E, Cunningham TJ, Asante EA, Brandner S, Collinge J, and Mead S
- Subjects
- Mice, Humans, Animals, Genome-Wide Association Study, Mice, Transgenic, Brain metabolism, Qa-SNARE Proteins genetics, Qa-SNARE Proteins metabolism, Creutzfeldt-Jakob Syndrome genetics, Creutzfeldt-Jakob Syndrome pathology, Prions genetics, Prions metabolism, Prion Diseases genetics, Prion Diseases pathology
- Abstract
Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrP
C ) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6-/- and Stx6+/- mice differed by 12 days relative to wildtype. Similarly, in Stx6-/- mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6-/- animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6-/- mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimer's disease., Competing Interests: Declaration of Competing Interest J.C. is a director and shareholder of D-Gen Limited, an academic spin-out company in the field of prion diagnosis, decontamination and therapeutics. There are no other competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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