Du Yunlan, Wang Fei, Zou Jing, Le Weidong, Dong Qing, Wang Zhiying, Shen Fei, Yu Ling, Li Yansheng
Department of Neurology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
Neurobiol Aging. 2014 Oct;35(10):2316-28. doi: 10.1016/j.neurobiolaging.2014.04.029. Epub 2014 May 2.
Abnormal aggregation of α-synuclein (α-syn) is central to the pathogenesis of Parkinson's disease (PD). Histone deacetylase 6 (HDAC6) was previously shown to control major cell response pathways to the cytotoxic ubiquitinated aggregates in some protein aggregation diseases. Whether it influences the aggregation process of α-syn in PD models and its related mechanisms are not completely known. Here, we characterized the expression and function of HDAC6 in the ubiquitin-proteasome system impairment-induced PD model. Our results showed that HDAC6 inhibition further exacerbated the nigrostriatal dopamine neurodegeneration and upregulated α-syn oligomers levels, whereas HDAC6 overexpression in vitro showed the opposite effects. More importantly, we provided evidence for the first time that HDAC6 regulating α-syn oligomers levels were related to its ability to trigger the heat shock response in a heat shock protein 90-dependent manner. HDAC6 mediated the dissociation of heat shock protein 90-heat shock factor 1-containing complex, and the activation of heat shock factor 1, which led to the expression of major molecular chaperones to prevent the deleterious α-syn aggregation. Thus, we propose that HDAC6 appears as a key modulator of cell protective response to the cytotoxic α-syn aggregates and may serve as a potential target for therapy development in PD.
α-突触核蛋白（α-syn）的异常聚集是帕金森病（PD）发病机制的核心。组蛋白去乙酰化酶6（HDAC6）先前已被证明在某些蛋白质聚集疾病中控制细胞对细胞毒性泛素化聚集体的主要反应途径。它是否影响PD模型中α-syn的聚集过程及其相关机制尚不完全清楚。在这里，我们表征了HDAC6在泛素-蛋白酶体系统损伤诱导的PD模型中的表达和功能。我们的结果表明，HDAC6抑制进一步加剧了黑质纹状体多巴胺能神经变性并上调了α-syn寡聚体水平，而体外HDAC6过表达则显示出相反的效果。更重要的是，我们首次提供证据表明HDAC6调节α-syn寡聚体水平与其以热休克蛋白90依赖性方式触发热休克反应的能力有关。HDAC6介导了热休克蛋白90-热休克因子1复合物的解离以及热休克因子1的激活，这导致主要分子伴侣的表达以防止有害的α-syn聚集。因此，我们提出HDAC6似乎是细胞对细胞毒性α-syn聚集体保护性反应的关键调节因子，并且可能作为PD治疗开发的潜在靶点。
