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

Abstract

Huntington disease (HD) is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (HTT). PolyQ length determines disease onset and severity with a longer expansion causing earlier onset. The mechanisms of mutant HTT-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in HD pathogenesis1,2. Here we tested whether mutant HTT impairs the mitochondrial fission/fusion balance and thereby causes neuronal injury. We show that mutant HTT triggers mitochondrial fragmentation in neurons and fibroblasts of HD individuals in vitro and HD mice in vivo before the presence of neurological deficits and HTT aggregates. Interestingly, mutant HTT abnormally interacts with the mitochondrial fission GTPase dynamin-related protein 1 (DRP1) in HD mice and individuals which in turn stimulates its enzymatic activity. Importantly, mutant HTT-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 DRP1K38A mutant. Thus, DRP1 might represent a new therapeutic target to combat neurodegeneration in HD.