Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity

    Authors

    W. J. Song; J. Chen; A. Petrilli; G. Liot; E. Klinglmayr; Y. Zhou; P. Poquiz; J. Tjong; M. A. Pouladi; M. R. Hayden; E. Masliah; M. Ellisman; I. Rouiller; R. Schwarzenbacher; B. Bossy; G. Perkins;E. Bossy-Wetzel

    Comments

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    Abbreviated Journal Title

    Nat. Med.

    Keywords

    S-NITROSYLATION; NITRIC-OXIDE; MOUSE MODEL; CELL-DEATH; DISEASE; NEURONS; NEURODEGENERATION; SUSCEPTIBILITY; FRAGMENTATION; DYSFUNCTION; Biochemistry & Molecular Biology; Cell Biology; Medicine, Research &; Experimental

    Abstract

    Huntington's disease is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (encoded by HTT). PolyQ length determines disease onset and severity, with a longer expansion causing earlier onset. The mechanisms of mutant huntingtin-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in Huntington's disease pathogenesis(1,2). Here we tested whether mutant huntingtin impairs the mitochondrial fission-fusion balance and thereby causes neuronal injury. We show that mutant huntingtin triggers mitochondrial fragmentation in rat neurons and fibroblasts of individuals with Huntington's disease in vitro and in a mouse model of Huntington's disease in vivo before the presence of neurological deficits and huntingtin aggregates. Mutant huntingtin abnormally interacts with the mitochondrial fission GTPase dynamin-related protein-1 (DRP1) in mice and humans with Huntington's disease, which, in turn, stimulates its enzymatic activity. Mutant huntingtin-mediated mitochondrial fragmentation, defects in anterograde and retrograde mitochondrial transport and neuronal cell death are all rescued by reducing DRP1 GTPase activity with the dominant-negative DRP1 K38A mutant. Thus, DRP1 might represent a new therapeutic target to combat neurodegeneration in Huntington's disease.

    Journal Title

    Nature Medicine

    Volume

    17

    Issue/Number

    3

    Publication Date

    1-1-2011

    Document Type

    Article

    Language

    English

    First Page

    377

    Last Page

    U181

    WOS Identifier

    WOS:000288070000050

    ISSN

    1078-8956

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