Multi-omic Insights into Molecular Mechanism and Therapeutic Targets in Spinocerebellar Ataxia type 7

The molecular mechanism in spinocerebellar ataxia type 7 is currently poorly understood. To provide understandings, a multi-omic study was performed using SCA7266Q/5Q mice. At week 12, entire brain tissue samples were collected and RNA sequencing, methylation analysis, and proteomic analysis were performed. Results were integrated to identify genes with identical trends in expression. Data was also compared with SCA patient serum proteomic analysis, and based on common differentially expressed proteins, a Naïve Bayesian network model was constructed to predict nilotinib treatment response. Data from RNA sequencing and methylation analysis revealed 58 significantly hypomethylated-upregulated genes and 62 hypermethylated-downregulated genes, mostly enriched in GO terms of regulation of axonogenesis, channel activity, and monoamine signaling. In the proteomic analysis, 211 upregulated and 281 downregulated DEPs associated mostly with immune response and cellular mobility were identified. Two genes, Fam107b and Tph2, showed differential expression in both transcriptomic and proteomic analysis. Forty-two overlapping proteins were identified compared with SCA patient serum, and Bayesian network analysis revealed that nilotinib treatment response was associated with the protein expression of CLU, CA2, GLUL, PRDX6, C1QA, PLXNB1, and age. These findings will serve as an important reference for future studies on the pathogenesis and discovery of druggable targets.