Zhu Min, Li Wen-Wei, Lu Chuan-Zhen
Laboratory of Neurology of Integrative Medical Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Neurology, Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, China; The State Key Laboratory of Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China.
CNS Neurosci Ther. 2014 Apr;20(4):308-16. doi: 10.1111/cns.12217. Epub 2013 Dec 19.
Parkinson's disease (PD) is a common neurodegenerative disease, characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. Recent investigations have shown that mitochondrial fragmentation, an early event during apoptosis, is implicated in the degeneration of DA neurons in PD, and more importantly, preventing mitochondrial fragmentation could rescue cell death in several PD models. Therefore, mitochondrial dynamics may be a therapeutic target for early intervention in PD. However, much remains unknown about the mechanism underlying mitochondrial fragmentation in PD.
The alterations in mitochondrial morphology, cell apoptosis, and mitochondrial shaping protein levels were detected after SH-SY5Y cells were treated with various doses of MPP+ or rotenone.
Mitochondrial fragmentation is an early event during apoptosis caused by MPP+ but not rotenone, and Trichostatin A (TSA), a commonly used histone deacetylase (HDAC) inhibitor, selectively rescues mitochondrial fragmentation and cell death induced by lower doses of MPP+. Mitochondrial fragmentation triggered by lower doses of MPP+ may be a result of Mfn2 down-regulation, which could be completely reversed by TSA. Further investigation suggests that TSA prevents MPP+-induced Mfn2 down-regulation via inhibiting histone deacetylation over Mfn2 promoter and alleviating its transcriptional dysfunction.
Histone deacetylase inhibitors prevent mitochondrial fragmentation and elicit early neuroprotection in PD cell model induced by MPP+. Hence, HDAC inhibitors may be a potential early treatment for PD.
帕金森病（PD）是一种常见的神经退行性疾病，其特征是黑质中多巴胺能（DA）神经元逐渐丧失。最近的研究表明，线粒体碎片化作为细胞凋亡过程中的早期事件，与PD中DA神经元的变性有关，更重要的是，在几种PD模型中，防止线粒体碎片化可以挽救细胞死亡。因此，线粒体动力学可能是PD早期干预的治疗靶点。然而，关于PD中线粒体碎片化的潜在机制仍有许多未知之处。
用不同剂量的MPP⁺或鱼藤酮处理SH-SY5Y细胞后，检测线粒体形态、细胞凋亡和线粒体塑形蛋白水平的变化。
线粒体碎片化是由MPP⁺而非鱼藤酮引起的细胞凋亡过程中的早期事件，常用的组蛋白去乙酰化酶（HDAC）抑制剂曲古抑菌素A（TSA）可选择性挽救低剂量MPP⁺诱导的线粒体碎片化和细胞死亡。低剂量MPP⁺触发的线粒体碎片化可能是Mfn2下调的结果，而TSA可使其完全逆转。进一步研究表明，TSA通过抑制Mfn2启动子上的组蛋白去乙酰化并减轻其转录功能障碍，防止MPP⁺诱导的Mfn2下调。
组蛋白去乙酰化酶抑制剂可防止MPP⁺诱导的PD细胞模型中的线粒体碎片化并引发早期神经保护作用。因此，HDAC抑制剂可能是PD的一种潜在早期治疗方法。
