Zhang Zhixiong, Wang Rui, Zhou Hui, Wu Dan, Cao Yifan, Zhang Chuang, Sun Hongyang, Mu Chenchen, Hao Zongbing, Ren Haigang, Wang Nana, Yu Shuang, Zhang Jingzhong, Tao Mengdan, Wang Can, Liu Yan, Liu Liu, Liu Yanli, Zang Jianye, Wang Guanghui
Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China.
Jiangsu Provincial Medical Innovation Center of Trauma Medicine, Institute of Trauma Medicine, Soochow University, Suzhou, 215123, Jiangsu, China.
Cell Mol Life Sci. 2024 Mar 12;81(1):128. doi: 10.1007/s00018-024-05176-5.
Epigenetic dysregulation that leads to alterations in gene expression and is suggested to be one of the key pathophysiological factors of Parkinson's disease (PD). Here, we found that α-synuclein preformed fibrils (PFFs) induced histone H3 dimethylation at lysine 9 (H3K9me2) and increased the euchromatic histone methyltransferases EHMT1 and EHMT2, which were accompanied by neuronal synaptic damage, including loss of synapses and diminished expression levels of synaptic-related proteins. Furthermore, the levels of H3K9me2 at promoters in genes that encode the synaptic-related proteins SNAP25, PSD95, Synapsin 1 and vGLUT1 were increased in primary neurons after PFF treatment, which suggests a linkage between H3K9 dimethylation and synaptic dysfunction. Inhibition of EHMT1/2 with the specific inhibitor A-366 or shRNA suppressed histone methylation and alleviated synaptic damage in primary neurons that were treated with PFFs. In addition, the synaptic damage and motor impairment in mice that were injected with PFFs were repressed by treatment with the EHMT1/2 inhibitor A-366. Thus, our findings reveal the role of histone H3 modification by EHMT1/2 in synaptic damage and motor impairment in a PFF animal model, suggesting the involvement of epigenetic dysregulation in PD pathogenesis.
表观遗传失调导致基因表达改变，被认为是帕金森病（PD）关键的病理生理因素之一。在此，我们发现α-突触核蛋白原纤维（PFFs）诱导组蛋白H3赖氨酸9位点二甲基化（H3K9me2），并增加常染色质组蛋白甲基转移酶EHMT1和EHMT2，这伴随着神经元突触损伤，包括突触丢失和突触相关蛋白表达水平降低。此外，PFF处理后原代神经元中编码突触相关蛋白SNAP25、PSD95、突触素1和囊泡谷氨酸转运体1（vGLUT1）的基因启动子处的H3K9me2水平升高，这表明H3K9二甲基化与突触功能障碍之间存在联系。用特异性抑制剂A-366或短发夹RNA（shRNA）抑制EHMT1/2可抑制组蛋白甲基化，并减轻PFF处理的原代神经元中的突触损伤。此外，用EHMT1/2抑制剂A-366处理可抑制注射PFFs的小鼠的突触损伤和运动障碍。因此，我们的研究结果揭示了EHMT1/2介导的组蛋白H3修饰在PFF动物模型的突触损伤和运动障碍中的作用，表明表观遗传失调参与了PD的发病机制。
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