Sodium butyrate attenuates rotenone-induced toxicity by activation of autophagy through epigenetically regulating PGC-1 alpha expression in PC12 cells

Short-chain fatty acids (SCFAs) are considered the key molecular link between gut microbiota and pathogenesis of Parkinson's disease (PD). However, the role of SCFAs in PD pathogenesis is controversial. Autophagy is important for the degradation of alpha-synuclein, which is critical to the development of PD. However, whether SCFAs can regulate autophagy in PD remains unknown. We aimed to investigate the role of SCFAs and explore the potential mechanisms in rat dopaminergic PC12 cells treated with rotenone. Expression levels of alpha-synuclein, peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) and microtubule-associated protein 1 light chain 3 beta (LC3B)-II were detected by Western blot. Histone acetylation levels at PGC-1 alpha promoter region were measured using chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR). Among the three SCFAs, sodium butyrate (NaB) protected against rotenone-induced toxicity. NaB activated autophagy pathway and reduced rotenone-induced alpha-synuclein expression through the activation of autophagy. Notably, NaB activated autophagy pathway through upregulating PGC-1 alpha expression. More importantly, NaB promoted the levels of histone 3 lysine 9 acetylation (H3K9Ac) and histone 3 lysine 27 acetylation (H3K27Ac) at PGC-1 alpha promoter region, indicating that NaB promotes PGC-1 alpha expression via histone acetylation modification. In conclusion, NaB can protect against rotenone-induced toxicity through activation of the autophagy pathway by upregulating PGC-1 alpha expression via epigenetic modification.