Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Pharmacol Res. 2020 Jan;151:104553. doi: 10.1016/j.phrs.2019.104553. Epub 2019 Nov 21.
Parkinson's disease (PD) that afflicts millions of individuals worldwide is associated with deposits of aggregate-prone proteins (e.g., α-synuclein) and with mitochondrial dysfunction in neuronal cells. Mitochondria are the main source of reactive oxygen species, provide energy for neuronal cells, and are regarded as dynamic organelles that are determined by mitochondrial fission, fusion, and mitophagy to maintain mitochondrial homeostasis. Growing evidence reveals that several dynamics-related proteins, such as dynamin-related protein 1 (Drp1), mediate mitochondrial fission, fusion, and mitophagy, to protect against neurodegeneration in PD. More importantly, not only is Drp1-mediated fission required for mitophagy that exerts a protective effect on neurons, but abnormal mitochondrial fission and mitophagy can drive neuronal survival or cell death (i.e., autophagy, apoptosis, and necroptosis), suggesting that Drp1 may play a pivotal role in the pathogenesis of PD. Also, PD-related proteins such as α-synuclein, leucine-rich repeat kinase-2, PTEN-induced putative kinase 1, and Parkin have been proven to interact with Drp1, thus contributing to mitochondrial dynamics and clearance, as well as neuronal fate. Here, we review the roles of Drp1 in mitochondrial fission, dynamics, mitophagy, bulk autophagy, apoptosis, and necroptosis for a better understanding of mitochondrial disturbances in PD-associated neurodegeneration and summarize the advances of novel chemical compounds targeting Drp1 to provide new insight into potential PD therapies.
帕金森病（PD）是一种全球性疾病，影响着全球数百万人，其与聚集倾向蛋白（如α-突触核蛋白）的沉积以及神经元细胞中线粒体功能障碍有关。线粒体是活性氧的主要来源，为神经元细胞提供能量，被认为是动态细胞器，通过线粒体分裂、融合和自噬来维持线粒体的动态平衡。越来越多的证据表明，几种与动力学相关的蛋白质，如与 dynamin 相关的蛋白 1（Drp1），介导线粒体分裂、融合和自噬，以防止 PD 中的神经变性。更重要的是，不仅 Drp1 介导的分裂对于发挥保护神经元作用的自噬是必需的，而且异常的线粒体分裂和自噬可以驱动神经元的存活或细胞死亡（即自噬、细胞凋亡和坏死性细胞死亡），这表明 Drp1 可能在 PD 的发病机制中发挥关键作用。此外，已经证明 PD 相关蛋白，如α-突触核蛋白、富含亮氨酸重复激酶 2、PTEN 诱导的假定激酶 1 和 Parkin，与 Drp1 相互作用，从而有助于线粒体动力学和清除以及神经元命运。在这里，我们综述了 Drp1 在线粒体分裂、动力学、自噬、自噬体、细胞凋亡和坏死性细胞死亡中的作用，以更好地理解 PD 相关神经变性中线粒体的紊乱，并总结了针对 Drp1 的新型化学化合物的进展，为潜在的 PD 治疗提供新的思路。
