CONICET- Universidad de Buenos Aires, Instituto de Química Biológica Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Laboratorio Interdisciplinario de Dinámica Celular y Nanoherramientas, Argentina.
CONICET- Universidad de Buenos Aires, Instituto de Química Biológica Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Laboratorio de Disfunción Celular en Enfermedades Neurodegenerativas y Nanomedicina, Buenos Aires, Argentina.
Mol Cell Neurosci. 2018 Apr;88:107-117. doi: 10.1016/j.mcn.2018.01.004. Epub 2018 Feb 3.
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.
帕金森病是一种神经退行性运动障碍，由黑质中多巴胺能神经元的丧失引起。其特征是路易小体的主要成分α-突触核蛋白的聚集。这种疾病的其他常见特征是线粒体功能障碍和自噬的激活/抑制，这两个事件都与α-突触核蛋白在细胞内的积累有关。这些事件导致神经退行性变的机制尚不清楚。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/线粒体自噬的影响。我们证明了野生型α-突触核蛋白的过表达会导致适度的毒性、ROS 生成和线粒体功能障碍。此外，α-突触核蛋白以 Drp-1 依赖的方式诱导线粒体碎片化。融合蛋白 Opa-1 的过表达可防止线粒体碎片化和细胞毒性。另一方面，表达α-突触核蛋白的细胞显示出激活的自噬，特别是线粒体自噬。采用遗传策略，我们证明自噬被触发是为了保护细胞免受α-突触核蛋白诱导的细胞死亡。我们的结果阐明了 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。所提出的发现表明了线粒体动态平衡和自噬在 PD 发病机制中的重要性。更好地理解这些过程之间的分子相互作用可能为 PD 的预防和改善提供新的治疗方法。
