Intracellular Trafficking SNARE Protein, Syntaxin-6, is a Modifier of Prion and Tau Pathogenesis in vivo and in Cellular Models

Abstract

Syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed risk factor for sporadic prion disease, progressive supranuclear palsy and Alzheimer's disease. However, no study has validated its functional role in these diseases, explored the disease stage at which it is acting nor its mechanism of action. Here, we show that syntaxin-6 acts at early stages of prion disease in experimental mice by increasing disease transmission risk following inoculation with low prion doses. Conversely, syntaxin-6 does not affect prion propagation kinetics or toxicity during established disease. Syntaxin-6 manipulation in cellular models profoundly alters the subcellular distribution and morphologies of disease-related PrP and modifies prion export. Furthermore, syntaxin-6 knockout in a transgenic tauopathy mouse model exerts protective effects on numerous physiological, behavioural and neuropathological outcome measures. Therefore, our studies firmly establish syntaxin-6 as a modifier of prion and tau pathogenesis, providing key insights into a fundamental mechanism of neurodegeneration.

Competing Interest Statement

J.C. is the director of D-Gen, Ltd., an academic spin-out company working in the field of prion disease diagnosis, decontamination and therapeutics. J.C. and G.S.J. are shareholders of D-Gen. D-Gen supplied the ICSM35 antibody used for PrP immunohistochemistry and ICSM18 antibody used for cell experiments. The other authors declare no competing interests.