Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
Behavioral and Functional Neuroscience Laboratory, Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
EMBO Mol Med. 2018 Mar;10(3). doi: 10.15252/emmm.201708166.
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.
生物能量衰竭和氧化应激是肌萎缩侧索硬化症（ALS）的常见病理特征，但这些特征是否可以有效地成为新的治疗干预靶点，仍需进一步确定。线粒体功能障碍与过度的线粒体裂变和碎片化有关，这是 ALS 病理的一个已知原因，而这种线粒体功能障碍主要是由 Drp1 的过度激活所介导的。在这里，我们确定了通过抑制 Drp1/Fis1 相互作用来抑制过度裂变是否会影响疾病的进展。我们观察到几种家族性 ALS 患者来源的成纤维细胞以及表达 SOD1 突变的培养运动神经元中存在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 Drp1/Fis1 相互作用，可显著降低活性氧水平，并改善线粒体结构和功能。从发病症状出现的第 90 天开始，用 P110 持续治疗表达 G93A SOD1 突变的小鼠，可改善运动性能和存活，这表明 Drp1 的过度激活可能是治疗 ALS 患者的一个有吸引力的靶点。
