Altered lipid homeostasis underlies selective neurodegeneration in SNX14 deficiency [1 yr]

Spinocerebellar Ataxia Autosomal Recessive 20 (SCAR20) is a rare disorder caused by mutation in the SNX14 gene. The symptoms of the disorder including coarse face, poor or lack of speech, delayed or absent of motor function, and most markedly, cerebella atrophy with Purkinje cell degeneration. SNX14 has been localized to ER and shown to play a vital role in facilitating the formation of lipid droplet and maintaining the lipid saturation balance in cell membrane. Meanwhile, it has also been localized to other subcellular organelles, including lysosome and endo-lysosome, and has been suggested to participate in the autophagy responses. However, the previous researches were performed in vitro or ex vivo, and how disrupted SNX14 led to Purkinje cell degeneration in the SCAR20 cerebella in vivo remained unexplored. Here, we report the first animal model that manifested the SCAR20 symptoms, by introducing a 1bp deletion in Snx14 in mice via CRISPR-Cas9. We performed RNAseq to analyse the pathway changes caused by Snx14 KO. We then performed gene expression profiling analysis using data obtained from RNA-seq of cerebella and cortices from 2-3 mice of SNX14 KO mice and their control littermates.