Department of Neurology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo, Tokyo, 113-8421, Japan.
Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science, 2-1-Hirosawa, Wako-Shi, Saitama, 351-0198, Japan.
J Neural Transm (Vienna). 2024 Dec;131(12):1415-1428. doi: 10.1007/s00702-024-02863-2. Epub 2024 Nov 25.
The exact cause of nigral cell death in Parkinson's disease (PD) is still unknown. However, research on MPTP-induced experimental parkinsonism has significantly advanced our understanding. In this model, it is widely accepted that mitochondrial respiratory failure is the primary mechanism of cell death. Studies have shown that a toxic metabolite of MPTP inhibits Complex I and alpha-ketoglutarate dehydrogenase activities in mitochondria. Since then, many research groups have focused on mitochondrial dysfunction in PD, identifying deficiencies in Complex I or III in PD patients' brains, skeletal muscle, and platelets. There is some debate about the decline in mitochondrial function in peripheral organs. However, since α-synuclein, the main component protein of Lewy bodies, accumulates in peripheral organs, it is reasonable to consider PD a systemic disease. Additionally, mutant mitochondrial DNA with a 4,977 base pair deletion has been found in the brains of PD patients, suggesting that age-related accumulation of deleted mtDNA is accelerated in the striatum and may contribute to the pathophysiology of PD. While the cause of PD remains unknown, mitochondrial dysfunction is undoubtedly a factor in cell death in PD. In addition, the causative gene for familial PD, parkin (now PRKN), and PTEN-induced putative kinase 1 (PINK1), both gene products are also involved in mitochondrial quality control. Moreover, we have successfully isolated and identified CHCHD2, which is involved in the mitochondrial electron transfer system. There is no doubt that mitochondrial dysfunction contributes to cell death in PD.
帕金森病（PD）中黑质细胞死亡的确切原因尚不清楚。然而，对 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的实验性帕金森病的研究极大地促进了我们对其的理解。在该模型中，普遍认为线粒体呼吸衰竭是细胞死亡的主要机制。研究表明，MPTP 的一种毒性代谢物抑制了线粒体中复合物 I 和α-酮戊二酸脱氢酶的活性。从那时起，许多研究小组专注于 PD 中的线粒体功能障碍，在 PD 患者的大脑、骨骼肌和血小板中发现复合物 I 或 III 缺陷。关于外周器官中线粒体功能下降存在一些争议。然而，由于α-突触核蛋白（Lewy 体的主要组成蛋白）在外周器官中积累，因此认为 PD 是一种全身性疾病是合理的。此外，在 PD 患者的大脑中发现了具有 4977 个碱基对缺失的突变线粒体 DNA，这表明与年龄相关的缺失 mtDNA 在纹状体中的积累加速，并可能导致 PD 的病理生理学。虽然 PD 的病因仍然未知，但线粒体功能障碍无疑是 PD 中细胞死亡的一个因素。此外，家族性 PD 的致病基因，即 parkin（现为 PRKN）和 PTEN 诱导的假定激酶 1（PINK1），这两种基因产物都参与了线粒体质量控制。此外，我们已经成功分离并鉴定了参与线粒体电子传递系统的 CHCHD2。毫无疑问，线粒体功能障碍导致 PD 中的细胞死亡。
