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Identification of Novel Therapeutic Targets for Polyglutamine Diseases That Target Mitochondrial Fragmentation
Annika Traa1,2,3, Emily Machiela4, Paige D Rudich1,2,3
1Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada.
Insights
Reducing mitochondrial fragmentation may treat polyglutamine diseases like Huntington's disease (HD). This study identified novel genetic targets in C. elegans that improve neuronal function and extend lifespan without disrupting the primary fission gene DRP1.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder linked to CAG repeat expansion.
- Mitochondrial dynamics and function are impaired in HD and other polyglutamine diseases.
- Targeting mitochondrial fission protein DRP1 shows promise but has drawbacks.
Purpose of the Study:
- To investigate the impact of reduced mitochondrial fragmentation on a neuronal model of polyglutamine toxicity in C. elegans.
- To identify novel genetic targets for mitigating neurodegeneration associated with polyglutamine diseases.
- To explore therapeutic strategies that avoid potential negative effects of DRP1 disruption.
Main Methods:
- Utilized a C. elegans neuronal model (Neur-67Q) exhibiting mitochondrial fragmentation and dysfunction.
- Disrupted the drp-1 gene to assess effects on mitochondrial morphology, movement, and longevity.
- Screened 24 RNA interference (RNAi) clones targeting genes involved in mitochondrial fragmentation.
Main Results:
- Neur-67Q worms displayed mitochondrial fragmentation in GABAergic neurons and reduced mitochondrial function.
- drp-1 disruption normalized mitochondrial morphology and rescued movement and longevity deficits.
- Eleven novel RNAi clones targeting different genes were identified that improved movement and lifespan.
Conclusions:
- Decreasing mitochondrial fragmentation is a potential therapeutic strategy for polyglutamine diseases.
- Novel genetic targets offer a way to reduce fragmentation without the risks of DRP1 inhibition.
- This research provides new avenues for treating neurodegenerative conditions like Huntington's disease.
Abstract:
Huntington's disease (HD) is one of at least nine polyglutamine diseases caused by a trinucleotide CAG repeat expansion, all of which lead to age-onset neurodegeneration. Mitochondrial dynamics and function are disrupted in HD and other polyglutamine diseases. While multiple studies have found beneficial effects from decreasing mitochondrial fragmentation in HD models by disrupting the mitochondrial fission protein DRP1, disrupting DRP1 can also have detrimental consequences in wild-type animals and HD models. In this work, we examine the effect of decreasing mitochondrial fragmentation in a neuronal C. elegans model of polyglutamine toxicity called Neur-67Q. We find that Neur-67Q worms exhibit mitochondrial fragmentation in GABAergic neurons and decreased mitochondrial function. Disruption of drp-1 eliminates differences in mitochondrial morphology and rescues deficits in both movement and longevity in Neur-67Q worms. In testing twenty-four RNA interference (RNAi) clones that decrease mitochondrial fragmentation, we identified eleven clones-each targeting a different gene-that increase movement and extend lifespan in Neur-67Q worms. Overall, we show that decreasing mitochondrial fragmentation may be an effective approach to treating polyglutamine diseases and we identify multiple novel genetic targets that circumvent the potential negative side effects of disrupting the primary mitochondrial fission gene drp-1.
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