Hill, Elizabeth Amy; (2024) The Role of Syntaxin-6 in Prion Diseases and Tauopathies. Doctoral thesis (Ph.D), UCL (University College London).

Text Final Thesis Nov 2024 Elizabeth Hill.pdf - Accepted Version Access restricted to UCL open access staff until 1 June 2025. Download (23MB)

Abstract

Variants in or near to the gene encoding syntaxin-6 (STX6), an intracellular trafficking protein, are proposed genetic risk factors for the most common human prion disease, sporadic Creutzfeldt-Jakob disease, and the primary tauopathy, progressive supranuclear palsy. The protein has also been implicated in Alzheimer’s disease with increased expression being the most likely genetic mechanism driving its risk effects across these neurodegenerative diseases. However, no study has functionally validated its role in prion or tau pathogenesis in vivo, explored the disease stage it is acting or its cellular mechanism of action. When infected with doses of prions which do not inevitably result in disease, syntaxin-6 knockout in vivo reduces the likelihood of disease development. In contrast, syntaxin-6 knockout has no, or minimal, effects on subsequent prion propagation or neurotoxicity during established disease. Collectively, this suggests that syntaxin-6 is acting at early stages of prion disease in vivo, modulating the establishment of prion infection. Furthermore, syntaxin-6 manipulation in cellular models profoundly alters prion-related phenotypes and the distribution of disease-related PrP, consistent with an intracellular trafficking phenomenon. Functionally, cellular studies support a role for syntaxin-6 in prion export, which may facilitate prion spread in vivo underlying the observed effects in mouse models. This work additionally investigated a potential shared role of syntaxin-6 in the pathobiology of tauopathies. Syntaxin-6 knockout in a transgenic tauopathy mouse model exerted protective effects on numerous function-related physiological, behavioural and neuropathological outcome measures. Furthermore, an altered distribution of pathological tau species was observed neuropathologically with syntaxin-6 knockout, despite total levels being comparable, in keeping with an intracellular trafficking phenomenon. Collectively, this work has validated syntaxin-6 as a modifier of both prion and tau pathogenesis acting predominantly at an early disease stage in vivo, in line with its risk discovery in human, and supports an intracellular trafficking mechanism of action.

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