Aromatic-Turmerone Analogs Activate Chaperone-Mediated Autophagy and Ameliorate Dendritic Shrinkage in Purkinje Cell Models of Spinocerebellar Ataxia

Abstract

We recently demonstrated that aromatic (ar)-turmerone analogs ((E)-5-methyl-1-(p-tolyl)hexa-1,4-dien-3-one [A2] and (E)-1-(4-methoxyphenyl)-5-methylhexa-1,4-dien-3-one [A4]) activate chaperone-mediated autophagy (CMA), a pathway in the autophagy-lysosome protein degradation system, in SH-SY5Y cells. Our previous studies revealed that the impairment of CMA and microautophagy (mA), another autophagy-related pathway, and dendritic shrinkage were observed in primary cultured Purkinje cells (PCs) expressing causal proteins of spinocerebellar ataxia (SCA), an autosomal dominant neurodegenerative disease. In the present study, we first investigated the effects of A2 and A4 on lysosomal protein degradation and dendritic morphology in cerebellar primary cultured PCs. Both compounds enhanced dendritic development and activated CMA in cultured PCs. These effects were significantly suppressed by the inhibitors of nuclear factor erythroid 2-related factor 2 and p38. We next examined the effects of A2 and A4 on PCs expressing several types of SCA-causing proteins (SCA model PCs). Both chemicals ameliorated the dendritic shrinkage and restored the decreased CMA/mA activity in several SCA model PCs. These findings suggest that the ar-turmerone analogs A2 and A4 improve the in vitro phenotype of SCA model PCs through CMA activation, highlighting the therapeutic potential of these analogs for various types of SCAs.