Inhibition of mitochondrial fragmentation diminishes Huntington's disease-associated neurodegeneration.
Huntington's disease (HD) is the result of expression of a mutated Huntingtin protein (mtHtt), and is associated with a variety of cellular dysfunctions including excessive mitochondrial fission. Here, we tested whether inhibition of excessive mitochondrial fission prevents mtHtt-induced pathology. We developed a selective inhibitor (P110-TAT) of the mitochondrial fission protein dynamin-related protein 1 (DRP1). We found that P110-TAT inhibited mtHtt-induced excessive mitochondrial fragmentation, improved mitochondrial function, and increased cell viability in HD cell culture models. P110-TAT treatment of fibroblasts from patients with HD and patients with HD with iPS cell-derived neurons reduced mitochondrial fragmentation and corrected mitochondrial dysfunction. P110-TAT treatment also reduced the extent of neurite shortening and cell death in iPS cell-derived neurons in patients with HD. Moreover, treatment of HD transgenic mice with P110-TAT reduced mitochondrial dysfunction, motor deficits, neuropathology, and mortality. We found that p53, a stress gene involved in HD pathogenesis, binds to DRP1 and mediates DRP1-induced mitochondrial and neuronal damage. Furthermore, P110-TAT treatment suppressed mtHtt-induced association of p53 with mitochondria in multiple HD models. These data indicate that inhibition of DRP1-dependent excessive mitochondrial fission with a P110-TAT-like inhibitor may prevent or slow the progression of HD.
Xing
X
Guo
Marie-Helene
MH
Disatnik
Marie
M
Monbureau
Mehrdad
M
Shamloo
Daria
D
Mochly-Rosen
Xin
X
Qi
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D003342:Corpus Striatum / Q000473:pathology; D004195:Disease Models, Animal; D034281:Dynamins / Q000037:antagonists & inhibitors*; D005347:Fibroblasts; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors*; D055879:Gene Knock-In Techniques; D057809:HEK293 Cells; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology; D057026:Induced Pluripotent Stem Cells / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors*; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors*; D058990:Molecular Targeted Therapy; D009410:Nerve Degeneration / Q000517:prevention & control; D016501:Neurites / Q000648:ultrastructure; D055495:Neurogenesis; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D011994:Recombinant Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; C486391:Dnm1l protein, mouse; D034281:Dynamins