Mutant protein kinase C gamma that causes spinocerebellar ataxia type 14 (SCA14) is selectively degraded by autophagy

Several causal missense mutations in the protein kinase Cγ (γPKC) gene have been found in spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously showed that mutant γPKC found in SCA14 is susceptible to aggregation and causes apoptosis. Aggregation of misfolded proteins is generally involved in the pathogenesis of many neurodegenerative diseases. Growing evidence indicates that macroautophagy (autophagy) is important for the degradation of misfolded proteins and the prevention of neurodegenerative diseases. In the present study, we examined whether autophagy is involved in the degradation of the mutant γPKC that causes SCA14. Mutant γPKC‐GFP was transiently expressed in SH‐SY5Y cells by using an adenoviral tetracycline‐regulated system. Subsequently, temporal changes in clearance of aggregates and degradation of γPKC‐GFP were evaluated. Rapamycin, an autophagic inducer, accelerated clearance of aggregates and promoted degradation of mutant γPKC‐GFP, but it did not affect degradation of wild‐type γPKC‐GFP. These effects of rapamycin were not observed in embryonic fibroblast cells from Atg5‐deficient mice, which are not able to perform autophagy. Furthermore, lithium, another type of autophagic inducer, also promoted the clearance of mutant γPKC aggregates. These results indicate that autophagy contributes to the degradation of mutant γPKC, suggesting that autophagic inducers could provide therapeutic potential for SCA14.