Targeting Mitochondrial Network Disorganization is Protective in C. elegans Models of Huntington’s Disease

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.

Molecular Pathophysiological Mechanisms in Huntington’s Disease

“…It is still a matter of debate whether the accumulation of mHtt on mitochondria, working as a docking receptor, is sufficient to increase the recruitment of Drp1 on the organelle, or if the interaction of mHtt with Drp1 alters the Drp1 cycling between mitochondria and the cytoplasm. However, by analyzing the mRNA levels of the various genes involved in mitochondrial dynamics, the expression of proteins related to mitochondrial fission, such as Drp1 and Fis1, was found increased, while the expression of fusion proteins (Mfn1, Mfn2, OPA1), was decreased proportionately with the stage of HD [ 232 ].…”

C. elegans as an Animal Model to Study the Intersection of DNA Repair, Aging and Neurodegeneration

“…et al, 2008), and mitochondrial depolarization (Panov et al, 2002). In a C. elegans model of HD, disruption of the mitochondrial fission gene drp-1 exacerbates the phenotype, whereas decreasing mitochondrial fragmentation improved protection (Machiela et al, 2021).…”

“…In Huntington’s disease (HD), adverse effects on mitochondria have been reported including mitochondrial electron transport impairment ( Brouillet et al, 2005 ), mitochondrial trafficking impairment ( Chang et al, 2006 ), ATP reduction in synaptic terminals ( Orr et al, 2008 ), and mitochondrial depolarization ( Panov et al, 2002 ). In a C. elegans model of HD, disruption of the mitochondrial fission gene drp-1 exacerbates the phenotype, whereas decreasing mitochondrial fragmentation improved protection ( Machiela et al, 2021 ).…”

Caenorhabditis elegans as a Model to Study Manganese-Induced Neurotoxicity

“…A multitude of neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are characterized by disruption in metal homeostasis and subsequent accumulation of disease-related protein aggregations [ 140 , 141 , 142 ]. In exploring Mn toxicity in C. elegans , we see a relationship between Mn and many neurodegenerative diseases.…”