Department of Neurology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Institute of Neurology, Sichuan Academy of Medical Sciences-Sichuan Provincial Hospital, Chengdu, China.
Neurochem Int. 2021 Oct;149:105141. doi: 10.1016/j.neuint.2021.105141. Epub 2021 Jul 21.
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.
组蛋白去乙酰化酶 6（HDAC6）已被证明可以控制某些蛋白质聚集疾病中细胞对细胞毒性泛素化聚集物的主要反应途径。然而，目前尚不清楚 HDAC6 是否会影响帕金森病（PD）中α-突触核蛋白（α-syn）的聚集过程。以前，我们证明 HDAC6 抑制通过热休克蛋白 90（Hsp90）依赖性方式加重 PD 小鼠模型中的黑质纹状体多巴胺神经退行性变并上调α-syn 寡聚体。在这里，我们进一步表明，HDAC6 过表达部分改善了 PD 模型的行为缺陷并减轻了黑质纹状体多巴胺（DA）神经元损伤。此外，发现 HDAC6 通过激活伴侣介导的自噬（CMA）来调节α-syn 寡聚体水平。在此过程中，Hsp90 去乙酰化介导了 HDAC6 和溶酶体相关膜蛋白 2A 之间的串扰。液相色谱-串联质谱和突变分析表明，Hsp90 在 K489 位点的乙酰化状态是 HDAC6 诱导的 CMA 激活，α-syn 寡聚体水平和 PD 细胞模型中细胞存活的重要决定因素。因此，我们的研究结果揭示了 HDAC6 在 PD 模型中的作用机制，即 HDAC6 通过调节 CMA 部分调节α-syn 寡聚体水平和 DA 神经元存活，并且 HDAC6 和 CMA 之间的串扰由 K489 位点的 Hsp90 去乙酰化介导。HDAC6 及其下游效应子似乎是细胞毒性α-syn 聚集物的关键调节剂，值得进一步研究以评估其作为 PD 潜在治疗靶点的价值。
