Parkinson's disease is a neurodegenerative movement disorder caused by the loss of dopaminergic neurons from substantia nigra. It is characterized by the accumulation of aggregated α-synuclein as the major component of the Lewy bodies. Additional common features of this disease are the mitochondrial dysfunction and the activation/inhibition of autophagy both events associated to the intracellular accumulation of α-synuclein. The mechanism by which these events contribute to neural degeneration remains unknown. In the present work we investigated the effect of α-synuclein on mitochondrial dynamics and autophagy/mitophagy in SH-SY5Y cells, an in vitro model of Parkinson disease. We demonstrated that overexpression of wild type α-synuclein causes moderated toxicity, ROS generation and mitochondrial dysfunction. In addition, α-synuclein induces the mitochondrial fragmentation on a Drp-1-dependent fashion. Overexpression of the fusion protein Opa-1 prevented both mitochondrial fragmentation and cytotoxicity. On the other hand, cells expressing α-synuclein showed activated autophagy and particularly mitophagy. Employing a genetic strategy we demonstrated that autophagy is triggered in order to protect cells from α-synuclein-induced cell death. Our results clarify the role of Opa-1 and Drp-1 in mitochondrial dynamics and cell survival, a controversial α-synuclein research issue. The findings presented point to the relevance of mitochondrial homeostasis and autophagy in the pathogenesis of PD. Better understanding of the molecular interaction between these processes could give rise to novel therapeutic methods for PD prevention and amelioration.

帕金森氏病是由黑质引起的多巴胺能神经元丢失引起的神经退行性运动障碍。其特征在于聚集的α-突触核蛋白的积累作为路易小体的主要成分。该疾病的其他共同特征是线粒体功能障碍和自噬的激活/抑制，这都是与α-突触核蛋白的细胞内蓄积有关的事件。这些事件促成神经变性的机制仍然未知。在本工作中，我们研究了α-突触核蛋白对帕金森病体外模型SH-SY5Y细胞中线粒体动力学和自噬/有丝分裂的影响。我们证明了野生型α-突触核蛋白的过度表达会引起中度毒性，ROS生成和线粒体功能障碍。此外，α-突触核蛋白以依赖于Drp-1的方式诱导线粒体片段化。融合蛋白Opa-1的过表达可防止线粒体片段化和细胞毒性。另一方面，表达α-突触核蛋白的细胞表现出活化的自噬，特别是线粒体。利用遗传策略，我们证明了自噬被触发以保护细胞免受α-突触核蛋白诱导的细胞死亡。我们的研究结果阐明了Opa-1和Drp-1在线粒体动力学和细胞存活中的作用，这是一个有争议的α-突触核蛋白研究问题。研究结果表明线粒体稳态和自噬在PD发病机理中的相关性。更好地了解这些过程之间的分子相互作用可能会导致预防和改善PD的新治疗方法。