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Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity
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Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity
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Journal Article
Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity
2011
Overview
Huntington's disease is characterized by mitochondrial dysfunction and neuron death. Now, Ella Bossy-Wetzel and her colleagues report that the aberrant interaction of mutant huntingtin protein with the mitochondrial fission protein DRP1 results in DRP1 activation. Blocking DRP1 activity can reduce mutant huntingtin–induced cell death.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Animals
/ Biomedical and Life Sciences
/ Dynamins
/ Enzymes
/ GTP Phosphohydrolases - metabolism
/ Humans
/ letter
/ Mice
/ Microtubule-Associated Proteins - metabolism
/ Mitochondrial Proteins - metabolism
/ Mutants
/ Mutation
/ Nerve Tissue Proteins - genetics
/ Nerve Tissue Proteins - metabolism
/ Neurons
/ Nuclear Proteins - metabolism
/ Proteins
