Title

Mutant Huntingtin Binds The Mitochondrial Fission Gtpase Dynamin-Related Protein-1 And Increases Its Enzymatic Activity

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. 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. © 2011 Nature America, Inc. All rights reserved.

Publication Date

3-1-2011

Publication Title

Nature Medicine

Volume

17

Issue

3

Number of Pages

377-383

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1038/nm.2313

Socpus ID

79952443408 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/79952443408

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