title: Inhibition of Drp1 hyper-activation is protective in animal models of experimental multiple sclerosis.
abstract: 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 H2O2. 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.
authors.affiliation: Department of Neurology, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, USA.
authors.forename: Fucheng
authors.initials: F
authors.lastname: Luo
authors.affiliation: Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
authors.forename: Karl
authors.initials: K
authors.lastname: Herrup
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, USA; Center for Mitochondria Diseases, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, USA. Electronic address: xxq38@case.edu.
authors.forename: Xin
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Neurology, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, USA; Center for Translational Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, USA. Electronic address: yxy33@case.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D034281:Dynamins / Q000378:metabolism*; D005260:Female; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D023421:Models, Animal; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism*; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011494:Protein Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: Drp1; Multiple sclerosis; Necroptosis; Oligodendrocytes