Characterisation and prion transmission study in mice with genetic reduction of sporadic Creutzfeldt-Jakob disease risk gene Stx6

Neurobiol Dis. 2023 Nov 21:106363. doi: 10.1016/j.nbd.2023.106363. Online ahead of print.ABSTRACTSporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrPC) 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 ob...

Source: Neurobiology of Disease - November 23, 2023 Category: Neurology Authors: Emma Jones Elizabeth Hill Jacqueline Linehan Tamsin Nazari Adam Caulder Gemma F Codner Marie Hutchison Matthew Mackenzie Michael Farmer Thomas Coysh Michael Wiggins De Oliveira Huda Al-Doujaily Malin Sandberg Emmanuelle Vir é Thomas J Cunningham Emmanuel Source Type: research