N-Terminal Mutant Huntingtin Associates with Mitochondria and Impairs Mitochondrial Trafficking

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.

Huntingtin protein interactions altered by polyglutamine expansion as determined by quantitative proteomic analysis

“…The biochemical interaction of N-terminal Htt fragments with mitochondria was previously demonstrated in HD knock-in mouse brain 46 and mutant Htt oligomers co-localize with mitochondrial proteins Mitochondrial dysfunction has been previously implicated in HD pathogenesis (reviewed in ref. 45), although the mechanism of Htt involvement is still elusive.…”

Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration

“…The age-related death of medium spiny GABAergic neurons of the striatum occurs in HD (52) and GABAergic Purkinje cells are significant targets for degeneration in the cerebellar ataxias (53). Recent studies have linked neuronal degeneration in HD to disrupted mitochondrial function (54). For example, exogenous CoQ is neuroprotective in mouse models of HD (55).…”

The Dynamics of the Mitochondrial Organelle as a Potential Therapeutic Target

“…76 mtHtt associated with mitochondria in a knock-in mouse model of HD, and inhibited mitochondrial trafficking in cultured neurons. 77 Song et al 78 also observed both increased fragmentation and decreased mobility of mitochondria in neurons expressing mtHtt, as well as a novel interaction between mtHtt and the fission-related protein Drp1 that led to an increase in the GTPase activity of Drp1. This increase in GTPase activity would give rise to increased fission.…”