HDAC6 regulates aggresome‐autophagy degradation pathway of α‐synuclein in response to MPP⁺‐induced stress

Abstract

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) a-synuclein (a-syn) and SH-SY5Y cells with MPP + . It was found that HDAC6 expression significantly increased and mainly colocalized with a-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 a-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 a-syn aggregates by regulating the aggresome-autophagy pathway. Understanding the mechanism may disclose potential therapeutic targets for synucleinopathies such as Parkinson's disease.

Application and interpretation of current autophagy inhibitors and activators

“…Mounting evidence suggests that although HDAC6 is not required for autophagy activation per se, it is critical for autophagosome-lysosome fusion [14,15] . Our recent findings showed that HDAC6 and dynein participated in the degradation of MPP + -induced misfolded α-synuclein aggregates by regulating the aggresome-autophagy pathway [16,17] .…”

The role of histone deacetylase 6 (HDAC6) in neurodegeneration

“…44 Recently, it was suggested that HDAC6-mediated protein degradation is protective in PD and dementia with Lewy bodies. 90 In this study, overexpression of mutant α-synuclein or 1-methyl-4-phenylpyridinium-induced neuronal stress significantly increases HDAC6 expression in PC-12 cells. 90 Likewise, HDAC6 inhibition reduces the autophagic response and the formation of Lewy bodies, followed by an impaired clearance of mutant α-synuclein.…”

“…90 In this study, overexpression of mutant α-synuclein or 1-methyl-4-phenylpyridinium-induced neuronal stress significantly increases HDAC6 expression in PC-12 cells. 90 Likewise, HDAC6 inhibition reduces the autophagic response and the formation of Lewy bodies, followed by an impaired clearance of mutant α-synuclein. 90 The protective nature of HDAC6 was confirmed by a study in Drosophila in which the endogenous Hdac6 protects dopaminergic neurons against cytotoxic α-synuclein aggregates by stimulating aggresome-like inclusion formation.…”

“…90 Likewise, HDAC6 inhibition reduces the autophagic response and the formation of Lewy bodies, followed by an impaired clearance of mutant α-synuclein. 90 The protective nature of HDAC6 was confirmed by a study in Drosophila in which the endogenous Hdac6 protects dopaminergic neurons against cytotoxic α-synuclein aggregates by stimulating aggresome-like inclusion formation. 91 Moreover, the E3 ligase parkin, mutated in autosomal recessive PD, mediates the polyubiquitination of DJ-1, which serves as a signal for HDAC6 to promote the sequestration of ubiquitinated aggregates into the aggresome.…”

Catechol Tetrahydroisoquinolines Enhance a-Synuclein Aggregation and Specify the Neurotoxicity to Dopaminergic Neurons

“…Similarly, Valproic acid, an inhibitor of histone deacetylase, counteracted the alteration of α-syn, the death of nigral neurons and the declined levels of striatal DA in the rotenone-treated rats [123]. Nevertheless, there were some evidences showing that the inhibition of HDAC6 exerted the detrimental effects including the accumulation of α-syn oligomers, the aggravated degeneration of nigrostriatal DA neurons and behavioral deficits [124][125][126]. In this line, HDAC or its inhibitors have been shown to exert effective roles in the inhibition of α-syn misfolding and treatment of PD.…”