title: Increased mitochondrial fission and neuronal dysfunction in Huntington's disease: implications for molecular inhibitors of excessive mitochondrial fission.
abstract: Huntington's disease (HD) is a fatal, progressive neurodegenerative disease with an autosomal dominant inheritance, characterized by chorea, involuntary movements of the limbs and cognitive impairments. Since identification of the HD gene in 1993, tremendous progress has been made in identifying underlying mechanisms involved in HD pathogenesis and progression, and in developing and testing molecular therapeutic targets, using cell and animal models of HD. Recent studies have found that mutant Huntingtin (mHtt) interacts with Dynamin-related protein 1 (Drp1), causing excessive fragmentation of mitochondria, leading to abnormal mitochondrial dynamics and neuronal damage in HD-affected neurons. Some progress has been made in developing molecules that can reduce excessive mitochondrial fission while maintaining both the normal balance between mitochondrial fusion and fission, and normal mitochondrial function in diseases in which excessive mitochondrial fission has been implicated. In this article, we highlight investigations that are determining the involvement of excessive mitochondrial fission in HD pathogenesis, and that are developing inhibitors of excessive mitochondrial fission for potential therapeutic applications.
authors.affiliation: Neurogenetics Laboratory, Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA; Department of Physiology and Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address: reddyh@ohsu.edu.
authors.forename: P Hemachandra
authors.initials: PH
authors.lastname: Reddy
mesh_terms: D000818:Animals; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins