Prevention of mitochondrial impairment by inhibition of protein phosphatase 1 activity in amyotrophic lateral sclerosis.
Prevention of mitochondrial impairment by inhibition of protein phosphatase 1 activity in amyotrophic lateral sclerosis.
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DOI：
10.1038/s41419-020-03102-8
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发表时间：
2020-10-21
影响因子：
9
通讯作者：
Sun W
中科院分区：
文献类型：
--
作者：
Choi SY;Lee JH;Chung AY;Jo Y;Shin JH;Park HC;Kim H;Lopez-Gonzalez R;Ryu JR;Sun W
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（MN）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相关，包括线粒体形态和功能的改变。然而，线粒体结构与ALS病理相关的分子机制知之甚少。在这项研究中，我们发现发动蛋白相关蛋白1（Drp 1）在几个ALS模型，包括那些与SOD 1和TDP-43突变，和蛋白磷酸酶1（PP 1）活性的病理诱导介导的去磷酸化在这些模型中。在原代神经元培养模型、iPSC衍生的人MN和体内斑马鱼模型中，PP 1-Drp 1级联的抑制有效地预防了ALS相关症状，包括线粒体片段化、线粒体复合物I损伤、轴突变性和细胞死亡。这些结果表明，PP 1-Drp 1活性的调节可能是ALS多种病理特征的治疗靶点。
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.
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影响因子：
11.1
作者：
Joshi AU;Saw NL;Vogel H;Cunnigham AD;Shamloo M;Mochly-Rosen D
通讯作者：
Mochly-Rosen D
影响因子：
25
作者：
Chou CC;Zhang Y;Umoh ME;Vaughan SW;Lorenzini I;Liu F;Sayegh M;Donlin-Asp PG;Chen YH;Duong DM;Seyfried NT;Powers MA;Kukar T;Hales CM;Gearing M;Cairns NJ;Boylan KB;Dickson DW;Rademakers R;Zhang YJ;Petrucelli L;Sattler R;Zarnescu DC;Glass JD;Rossoll W
通讯作者：
Rossoll W
DOI：
10.1126/science.aaa4484
发表时间：
2015-04-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Das I;Krzyzosiak A;Schneider K;Wrabetz L;D'Antonio M;Barry N;Sigurdardottir A;Bertolotti A
通讯作者：
Bertolotti A
影响因子：
16
作者：
Cho, Hyo Min;Ryu, Jae Ryun;Sun, Woong
通讯作者：
Sun, Woong
影响因子：
4
作者：
Coussee, Evelyne;De Smet, Patrick;Callewaert, Geert
通讯作者：
Callewaert, Geert