HDAC6 regulates aggresome-autophagy degradation pathway of α-synuclein in response to MPP plus -induced stress

P>Increasing evidence suggests that the ubiquitin-binding histone deacetylase-6 (HDAC6) plays an important role in the clearance of misfolded proteins by autophagy. In this study, we treated PC-12 cells over-expressing human mutant (A53T) alpha-synuclein (alpha-syn) and SH-SY5Y cells with MPP+. It was found that HDAC6 expression significantly increased and mainly colocalized with alpha-syn in the perinuclear region to form aggresome-like bodies. HDAC6 deficiency blocked the formation of aggresome-like bodies and interfered with the autophagy in response to MPP+-induced stress. Moreover, misfolded alpha-syn accumulated into the nuclei, resulting in its reduced clearance, and finally, the number of apoptotic cells significantly increased. Taken together, HDAC6 participated in the degradation of MPP+-induced misfolded alpha-syn aggregates by regulating the aggresome-autophagy pathway. Understanding the mechanism may disclose potential therapeutic targets for synucleinopathies such as Parkinson's disease.