Abstract
Huntington’s disease (HD) is an adult-onset neurodegenerative disease caused by a trinucleotide CAG repeat expansion in the HTT gene. While the pathogenesis of HD is incompletely understood, mitochondrial dysfunction is thought to be a key contributor. In this work, we used C. elegans models to elucidate the role of mitochondrial dynamics in HD. We found that expression of a disease-length polyglutamine tract in body wall muscle, either with or without exon 1 of huntingtin, results in mitochondrial fragmentation and mitochondrial network disorganization. While mitochondria in young HD worms form elongated tubular networks as in wild-type worms, mitochondrial fragmentation occurs with age as expanded polyglutamine protein forms aggregates. To correct the deficit in mitochondrial morphology, we reduced levels of DRP-1, the GTPase responsible for mitochondrial fission. Surprisingly, we found that disrupting drp-1 can have detrimental effects, which are dependent on how much expression is decreased. To avoid potential negative side effects of disrupting drp-1, we examined whether decreasing mitochondrial fragmentation by targeting other genes could be beneficial. Through this approach, we identified multiple genetic targets that rescue movement deficits in worm models of HD. Three of these genetic targets, pgp-3, F25B5.6 and alh-12, increased movement in the HD worm model and restored mitochondrial morphology to wild-type morphology. This work demonstrates that disrupting the mitochondrial fission gene drp-1 can be detrimental in animal models of HD, but that decreasing mitochondrial fragmentation by targeting other genes can be protective. Overall, this study identifies novel therapeutic targets for HD aimed at improving mitochondrial health.
Highlights
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by an expansion of the polyglutamine tract in the N-terminal of the huntingtin (Htt) protein
In order to examine the effect of RNA interference (RNAi) clones on mitochondrial morphology in mitoRFP;rol-6 and BWHtt74Q;mitoRFP;rol-6 worms, 30 L4 worms were picked to plates seeded with empty vector (EV), pgp-3, F25B5.6, and alh-12 RNAi-expressing bacteria
We show that C. elegans models of HD exhibit mitochondrial fragmentation and disorganized mitochondrial networks, which are associated with polyglutamine aggregation
Summary
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by an expansion of the polyglutamine tract in the N-terminal of the huntingtin (Htt) protein. Examination of mitochondria by electron microscopy in brain sections from R6/2 mice [20] and YAC128 mice [17] revealed the presence of smaller mitochondria in HD mice compared to controls, suggesting that increased mitochondrial fragmentation occurs in vivo In these studies, it has been shown that the expression of exon 1 fragments of mutant Htt is sufficient to cause mitochondrial fragmentation [16,17,18]. While the precise mechanism by which mutant Htt causes mitochondrial fragmentation is still unclear, contributing factors may include: alterations in expression levels of fission and fusion proteins [20, 24, 25], an increase in DRP-1 enzymatic activity resulting from increased interaction with mutant Htt [17, 26], increased S-nitrosylation of DRP-1 leading to increased fission activity [18], increased levels of reactive oxygen species [22, 27], decreased Nrf signaling [20], and increased calcineurin activity [23]
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