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N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking.

TitleN-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking.
Publication TypeJournal Article
Year of Publication2008
AuthorsOrr AL, Li S, Wang C-E, Li H, Wang J, Rong J, Xu X, Mastroberardino PGiorgio, J Greenamyre T, Li X-J
JournalJ Neurosci
Volume28
Issue11
Pagination2783-92
Date Published2008 Mar 12
ISSN1529-2401
KeywordsAnimals, Cell Line, Cells, Cultured, Humans, Huntingtin Protein, Huntington Disease, Mice, Mice, Mutant Strains, Mitochondria, Mutation, Nerve Tissue Proteins, Nuclear Proteins, Peptide Fragments, Protein Transport
Abstract

Huntington's disease (HD) is caused by polyglutamine (polyQ) expansion in huntingtin (htt), a large (350 kDa) protein that localizes predominantly to the cytoplasm. Proteolytic cleavage of mutant htt yields polyQ-containing N-terminal fragments that are prone to misfolding and aggregation. Disease progression in HD transgenic models correlates with age-related accumulation of soluble and aggregated forms of N-terminal mutant htt fragments, suggesting that multiple forms of mutant htt are involved in the selective neurodegeneration in HD. Although mitochondrial dysfunction is implicated in the pathogenesis of HD, it remains unclear which forms of cytoplasmic mutant htt associate with mitochondria to affect their function. Here we demonstrate that specific N-terminal mutant htt fragments associate with mitochondria in Hdh(CAG)150 knock-in mouse brain and that this association increases with age. The interaction between soluble N-terminal mutant htt and mitochondria interferes with the in vitro association of microtubule-based transport proteins with mitochondria. Mutant htt reduces the distribution and transport rate of mitochondria in the processes of cultured neuronal cells. Reduced ATP level was also found in the synaptosomal fraction isolated from Hdh(CAG)150 knock-in mouse brain. These findings suggest that specific N-terminal mutant htt fragments, before the formation of aggregates, can impair mitochondrial function directly and that this interaction may be a novel target for therapeutic strategies in HD.

DOI10.1523/JNEUROSCI.0106-08.2008
Alternate JournalJ. Neurosci.
PubMed ID18337408
PubMed Central IDPMC2652473
Grant ListR01 NS041669 / NS / NINDS NIH HHS / United States
R01 AG019206 / AG / NIA NIH HHS / United States
R01 AG019206-07 / AG / NIA NIH HHS / United States
R01 NS045016 / NS / NINDS NIH HHS / United States
AG19206 / AG / NIA NIH HHS / United States
R01 AG031153 / AG / NIA NIH HHS / United States
NS41669 / NS / NINDS NIH HHS / United States