Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis.
Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis.
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DOI：
10.15252/emmm.201708166
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发表时间：
2018-03
影响因子：
11.1
通讯作者：
Mochly-Rosen D
中科院分区：
文献类型：
--
作者：
Joshi AU;Saw NL;Vogel H;Cunnigham AD;Shamloo M;Mochly-Rosen D
生物能量衰竭和氧化应激是肌萎缩侧索硬化症（ALS）的常见病理标志，但这些是否可以有效地靶向新的治疗干预需要确定。据报道，ALS病理学的贡献者之一是与过度线粒体分裂和片段化相关的线粒体功能障碍，这主要是由Drp 1超活化介导的。在这里，我们确定是否通过抑制Drp 1/Fis 1相互作用来抑制过度裂变影响疾病进展。我们在几种家族形式的ALS患者来源的成纤维细胞以及表达SOD 1突变体的培养运动神经元中观察到线粒体过度碎片化和功能障碍。在这两种细胞模型中，通过选择性肽抑制剂P110抑制Drp 1/Fis 1相互作用，导致活性氧水平显著降低，并改善线粒体结构和功能。在第90天疾病症状发作时开始用P110持续治疗表达G93 A SOD 1突变的小鼠，产生了运动性能和存活率的改善，这表明Drp 1过度激活可能是治疗ALS患者的一个有吸引力的靶点。
Bioenergetic failure and oxidative stress are common pathological hallmarks of amyotrophic lateral sclerosis (ALS), but whether these could be targeted effectively for novel therapeutic intervention needs to be determined. One of the reported contributors to ALS pathology is mitochondrial dysfunction associated with excessive mitochondrial fission and fragmentation, which is predominantly mediated by Drp1 hyperactivation. Here, we determined whether inhibition of excessive fission by inhibiting Drp1/Fis1 interaction affects disease progression. We observed mitochondrial excessive fragmentation and dysfunction in several familial forms of ALS patient‐derived fibroblasts as well as in cultured motor neurons expressing SOD1 mutant. In both cell models, inhibition of Drp1/Fis1 interaction by a selective peptide inhibitor, P110, led to a significant reduction in reactive oxygen species levels, and to improvement in mitochondrial structure and functions. Sustained treatment of mice expressing G93A SOD1 mutation with P110, beginning at the onset of disease symptoms at day 90, produced an improvement in motor performance and survival, suggesting that Drp1 hyperactivation may be an attractive target in the treatment of ALS patients.