Department of Anatomy, Korea University College of Medicine, Brain Korea 21 plus, Seoul, 02841, Republic of Korea.
Department of Neurology, University of Massachusetts Medical school, Worcester, MA, USA.
Cell Death Dis. 2020 Oct 21;11(10):888. doi: 10.1038/s41419-020-03102-8.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of motor neurons (MNs) and subsequent muscle weakness. These pathological features are associated with numerous cellular changes, including alteration in mitochondrial morphology and function. However, the molecular mechanisms associating mitochondrial structure with ALS pathology are poorly understood. In this study, we found that Dynamin-related protein 1 (Drp1) was dephosphorylated in several ALS models, including those with SOD1 and TDP-43 mutations, and the dephosphorylation was mediated by the pathological induction of protein phosphatase 1 (PP1) activity in these models. Suppression of the PP1-Drp1 cascade effectively prevented ALS-related symptoms, including mitochondrial fragmentation, mitochondrial complex I impairment, axonal degeneration, and cell death, in primary neuronal culture models, iPSC-derived human MNs, and zebrafish models in vivo. These results suggest that modulation of PP1-Drp1 activity may be a therapeutic target for multiple pathological features of ALS.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，由运动神经元（MNs）的进行性丧失和随后的肌肉无力引起。这些病理特征与许多细胞变化有关，包括线粒体形态和功能的改变。然而，与线粒体结构与 ALS 病理学相关的分子机制尚不清楚。在这项研究中，我们发现肌萎缩侧索硬化症几种模型（包括 SOD1 和 TDP-43 突变的模型）中的 Drp1 去磷酸化，这种去磷酸化是由这些模型中蛋白磷酸酶 1（PP1）活性的病理性诱导介导的。在原代神经元培养模型、iPSC 衍生的人类 MNs 和体内斑马鱼模型中，抑制 PP1-Drp1 级联反应可有效预防与肌萎缩侧索硬化症相关的症状，包括线粒体碎片化、线粒体复合物 I 损伤、轴突变性和细胞死亡。这些结果表明，调节 PP1-Drp1 活性可能是肌萎缩侧索硬化症多种病理特征的治疗靶点。
