HDAC6-mediated Hsp90 deacetylation reduces aggregation and toxicity of the protein alpha-synuclein by regulating chaperone-mediated autophagy

• Published in: Neurochemistry international 2021-10, Vol.149, p.105141-105141, Article 105141
• Main Authors: Du, Yunlan, Yang, Xiao, Li, Zezhi, Le, Weidong, Hao, Yong, Song, Yeping, Wang, Fei, Guan, Yangtai
• Format: Article
• Language: English
• Subjects: Acetylcysteine - analogs & derivatives; Acetylcysteine - toxicity; alpha-Synuclein - antagonists & inhibitors; alpha-Synuclein - metabolism; Animals; Chaperone-mediated autophagy; Chaperone-Mediated Autophagy - drug effects; Chaperone-Mediated Autophagy - physiology; Heat shock protein 90; Histone deacetylase 6; Histone Deacetylase 6 - metabolism; HSP90 Heat-Shock Proteins - metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Parkinson's disease; Parkinsonian Disorders - chemically induced; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - pathology; Protein Aggregates - drug effects; Protein Aggregates - physiology; α-synuclein
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2021.105141

Histone deacetylase 6 (HDAC6) has been shown to control major cell response pathways to the cytotoxic ubiquitinated aggregates in some protein aggregation diseases. However, it is not well known whether HDAC6 affects the aggregation process of α-synuclein (α-syn) in Parkinson's disease (PD). Previously, we demonstrated that HDAC6 inhibition exacerbated the nigrostriatal dopamine neurodegeneration and up-regulated α-syn oligomers in a heat shock protein 90 (Hsp90)-dependent manner in PD mouse model. Here, we further showed that HDAC6 overexpression partly improved the behavior deficits of the PD model and alleviated the nigrostriatal dopamine (DA) neurons injury. Furthermore, HDAC6 was found to regulate α-syn oligomers levels through activation of chaperone-mediated autophagy (CMA). During this process, Hsp90 deacetylation mediated the crosstalk between HDAC6 and lysosome-associated membrane protein type 2A. Liquid chromatography-tandem mass spectrometry and mutational analysis showed that acetylation status Hsp90 at the K489 site was a strong determinant for HDAC6-induced CMA activation, α-syn oligomers levels, and cell survival in the cell model of PD. Therefore, our findings uncovered the mechanism of HDAC6 in the PD model that HDAC6 regulated α-syn oligomers levels and DA neurons survival partly through modulating CMA, and Hsp90 deacetylation at the K489 site mediated the crosstalk between HDAC6 and CMA. HDAC6 and its downstream effectors appear as key modulators of the cytotoxic α-syn aggregates, which deserve further investigations to evaluate their values as potential therapeutic targets in PD. •HDAC6 regulates α-synuclein oligomers levels and nigrostriatal dopamine neurons survival in a mouse model of PD.•HDAC6 overexpression mildly improved the behavior deficits of the PD mouse model.•HDAC6 regulates α-synuclein oligomers levels through modulating CMA.•Hsp90 deacetylation mediates the crosstalk between HDAC6 and CMA.•Acetylation status of Hsp90 at the K489 site was a strong determinant for this crosstalk and α-synuclein oligomer levels.