Department of Biochemistry and Neurobiology and Institute of Health Sciences, Gyeongsang National University School of Medicine, 92 Chilam-Dong, Jinju, GyeongNam 660-751, Republic of Korea.
Neurosci Lett. 2010 Mar 12;472(1):47-52. doi: 10.1016/j.neulet.2010.01.053. Epub 2010 Feb 1.
Loss of dopaminergic cells induced by alpha-synuclein accumulation in substantia nigra causes the development of Parkinson's disease (PD). To date, although autophagy has been implicated in the pathology of PD, the molecular mechanism is still unclear. To study the role of autophagy in PD pathogenesis, we established stable SH-SY5Y cell lines overexpressing wild-type or mutant alpha-synuclein proteins (A30P or A53T). Overexpression of mutant alpha-synuclein induced some protein aggregates and cell death in the absence of drug. LC3-II protein, a critical marker for autophagy, was produced in an autophagy-dependent manner. The rotenone-induced cell death was interrupted by autophagy stimulation. Autophagy activation also restored the mitochondrial membrane potential (MMP) impaired by rotenone in mutant alpha-synuclein expressing cells. Additionally, autophagy activation significantly relieved rotenone-induced ROS accumulation and HIF-1alpha expression in neuronal cells expressing mutant alpha-synuclein proteins. These findings indicate that autophagy plays an important scavenger role against harmful influence of toxic protein aggregates produced in rotenone-treated cells.
在黑质中由于α-突触核蛋白积累导致多巴胺能细胞的丧失会引发帕金森病（PD）。迄今为止，尽管自噬已被牵涉到 PD 的病理学中，但分子机制仍不清楚。为了研究自噬在 PD 发病机制中的作用，我们建立了稳定过表达野生型或突变型α-突触核蛋白（A30P 或 A53T）的 SH-SY5Y 细胞系。突变型α-突触核蛋白的过表达在没有药物的情况下诱导了一些蛋白质聚集体和细胞死亡。LC3-II 蛋白是自噬的关键标志物，以自噬依赖性的方式产生。自噬的刺激中断了鱼藤酮诱导的细胞死亡。自噬的激活也恢复了在表达突变型α-突触核蛋白的细胞中鱼藤酮损伤的线粒体膜电位（MMP）。此外，自噬的激活显著减轻了神经元细胞中由突变型α-突触核蛋白蛋白产生的鱼藤酮诱导的 ROS 积累和 HIF-1alpha 表达。这些发现表明，自噬在清除鱼藤酮处理细胞中产生的有毒蛋白质聚集体的有害影响方面发挥了重要的清除作用。
