Knockout of Sporadic Creutzfeldt-Jakob Disease Risk Gene Stx6 in Mice Extends Prion Disease Incubation Time

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common human prion disease, which occurs when the cellular prion protein (PrPC) spontaneously misfolds into disease-associated forms, 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 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 time and prion-related neuropathology. Homozygous (Stx6-/-) and heterozygous (Stx6+/-) knockout of Stx6 expression extended survival by 12 days following inoculation with RML prions relative to wildtype controls. Similarly, in Stx6-/- mice, disease incubation time following inoculation with ME7 prions was extended 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 confirmatory evidence for a pathological role of Stx6 expression in prion disease and support further exploration of syntaxin-6 lowering as a potential therapeutic strategy.