Jones, Emma Louise; (2022) The role of STX6 in sporadic Creutzfeldt-Jakob disease and related neurodegenerative diseases. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common human prion disease, in which the cellular prion protein (PrPC) appears to spontaneously misfold and aggregate into a disease-associated form leading to invariably fatal neurodegeneration. Although there is clear genetic control in sCJD, no loci except PRNP (encoding PrPC) have previously been consistently significant in genetic studies. Through international collaboration a two-stage genome wide association study (GWAS) was conducted for sCJD risk analysing a total of 5,208 cases and 511,585 matched control individuals from 11 countries. This thesis describes the first replicated association of two novel loci alongside PRNP, with variants in or near STX6 (encoding syntaxin-6) and GAL3ST1 (encoding cerebroside sulfotransferase), as conferring risk for sCJD at genome-wide significance in populations with European ancestry. With a focus hereafter on elucidating the casual gene and functional mechanisms at the STX6 locus, fine-mapping and integration of publically-available expression quantitative trait loci databases provides evidence for increased STX6 expression in the caudate and putamen as driving this association. RNA silencing in immortalised cell lines and CRISPR-mediated gene knockout in human iPS-derived cortical neurons and mice were used to model the biological mechanism of syntaxin-6 in prion propagation and cell biology with a particular focus on its role in the endolysosomal system. Knockout and hemizygous expression of Stx6 in C57BL/6 mice modestly extends survival time following inoculation with mouse-adapted scrapie prion strains RML and ME7, supporting the genetic association of STX6 expression in patients. Identification of non-PRNP loci associated with sCJD risk provides new insight into disease mechanisms and offers potential additional targets for therapeutic intervention. Furthermore the previous implication of STX6 in related neurodegenerative diseases such as the tauopathy progressive supranuclear palsy indicates a possible shared role of syntaxin-6 in the pathobiology of other “prion-like” proteins and disorders.

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