Fig. 5.

SFK dysregulation occurs in multiple SCAs. (A) Western blot of whole-cerebellum lysate from 15-wk-old mice shows a 95% reduction of in the band that corresponds to MTSS1 in ATXN1^Q82 mice but only a 50% reduction in calbindin. Tubulin is included as a loading control. (B) Western blot of cerebellum lysate from 4-wk-old MIM^EX15 mice shows no change in phospho-serine776 ATXN1 levels. (C) RNA-sequencing from ATXN1^Q82 cerebella shows reduced fragments per kilobase of transcript per million mapped reads for Mtss1 mRNA in samples from 12-wk-old and 28-wk-old mice (*q < 0.005). (D) Mean firing frequency values (in Hertz) for WT and ATXN1^Q82 mice, with and without dasatinib (Das) treatment. *P = 0.0094, one-way ANOVA with Tukey post hoc test. Error bars indicate SEM. (E) Western blot of whole-cerebellum lysate from 3-wk-old mice shows no change in MTSS1 in βIII-spectrin^−/− mice, but active SFK-Y416 phosphorylation is increased. Calbindin and total Src are included as loading controls. (F) Mean firing frequency values (in Hertz) for wild-type and βIII-spectrin−/− mice, with and without dasatinib treatment. *P < 0.05, one-way ANOVA, Tukey post hoc test. Error bars indicate SEM. (G) SPTNB2 abundance is not changed in 4-wk-old MIMEX15 mice. (H) βIII-spectrin levels are reduced 40% in 24-wk-old ATXN2Q127 mice. (I) A model in which pathogenic alleles of ATNX1 (ATXN1^Q82) and ATXN2 (ATXN2^Q42) prevent the accumulation of MTSS1 and SPTBN2 which restrain SFK activity to prevent abnormal firing patterns and neurodegeneration.