Mutant protein kinase C gamma that causes spinocerebellar ataxia type 14 (SCA14) is selectively degraded by autophagy
- 21 April 2010
- journal article
- Published by Wiley in Genes to Cells
- Vol. 15 (5), 425-438
- https://doi.org/10.1111/j.1365-2443.2010.01395.x
Abstract
Several causal missense mutations in the protein kinase Cgamma (gammaPKC) gene have been found in spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously showed that mutant gammaPKC 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 gammaPKC that causes SCA14. Mutant gammaPKC-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 gammaPKC-GFP were evaluated. Rapamycin, an autophagic inducer, accelerated clearance of aggregates and promoted degradation of mutant gammaPKC-GFP, but it did not affect degradation of wild-type gammaPKC-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 gammaPKC aggregates. These results indicate that autophagy contributes to the degradation of mutant gammaPKC, suggesting that autophagic inducers could provide therapeutic potential for SCA14.Keywords
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