Luo Fucheng, Herrup Karl, Qi Xin, Yang Yan
Department of Neurology, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, USA.
Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
Exp Neurol. 2017 Jun;292:21-34. doi: 10.1016/j.expneurol.2017.02.015. Epub 2017 Feb 24.
Multiple Sclerosis (MS), a leading neurological disorder of young adults, is characterized by the loss of oligodendrocytes (OLs), demyelination, inflammation and neuronal degeneration. Here we show that dynamin-related protein 1 (Drp1), a mitochondrial fission protein, is activated in primary OL cells exposed to TNF-α induced inflammation or oxidative stress, as well as in EAE-immunized and cuprizone toxicity-induced demyelinating mouse models. Inhibition of Drp1 hyper-activation by the selective inhibitor P110 abolishes Drp1 translocation to the mitochondria, reduces mitochondrial fragmentation and stems necrosis in primary OLs exposed to TNF-α and HO. Notably, in both types of mouse models, treatment with P110 significantly reduces the loss of mature OLs and demyelination, attenuates the number of active microglial cells and astrocytes, yet has no effect on the differentiation of oligodendrocyte precursor cells. Drp1 activation appears to be mediated through the RIPK1/RIPK3/MLKL/PGAM5 pathway during TNF-α-induced oligodendroglia necroptosis. Our results demonstrate a critical role of Drp1 hyper-activation in OL cell death and suggest that an inhibitor of Drp1 hyper-activation such as P110 is worth exploring for its ability to halt or slow the progression of MS.
多发性硬化症（MS）是年轻人中主要的神经疾病，其特征为少突胶质细胞（OLs）丧失、脱髓鞘、炎症和神经元变性。我们在此表明，动力蛋白相关蛋白1（Drp1），一种线粒体分裂蛋白，在暴露于肿瘤坏死因子-α（TNF-α）诱导的炎症或氧化应激的原代OL细胞中被激活，以及在实验性自身免疫性脑脊髓炎（EAE）免疫和铜螯合剂毒性诱导的脱髓鞘小鼠模型中被激活。选择性抑制剂P110对Drp1过度激活的抑制消除了Drp1向线粒体的转位，减少了线粒体碎片化，并阻止了暴露于TNF-α和过氧化氢（HO）的原代OLs中的坏死。值得注意的是，在两种小鼠模型中，用P110治疗显著减少了成熟OLs的丧失和脱髓鞘，减少了活跃的小胶质细胞和星形胶质细胞的数量，但对少突胶质细胞前体细胞的分化没有影响。在TNF-α诱导的少突胶质细胞坏死性凋亡过程中，Drp1激活似乎是通过RIPK1/RIPK3/MLKL/PGAM5途径介导的。我们的结果证明了Drp1过度激活在OL细胞死亡中的关键作用，并表明像P110这样的Drp1过度激活抑制剂因其能够阻止或减缓MS的进展而值得探索。
