RRC ID 76076
Author Traa A, Machiela E, Rudich PD, Soo SK, Senchuk MM, Van Raamsdonk JM.
Title Identification of Novel Therapeutic Targets for Polyglutamine Diseases That Target Mitochondrial Fragmentation.
Journal Int J Mol Sci
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.
Volume 22(24)
Published 2021-12-14
DOI 10.3390/ijms222413447
PII ijms222413447
PMID 34948242
PMC PMC8703635
MeSH Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Disease Models, Animal Drug Delivery Systems GABAergic Neurons / metabolism* Humans Huntington Disease / drug therapy Huntington Disease / genetics Huntington Disease / metabolism* Mitochondria / genetics Mitochondria / metabolism* Mitochondrial Dynamics* Mitochondrial Proteins / genetics Mitochondrial Proteins / metabolism RNA Interference
Resource
C.elegans tm1108