title: Oxidative stress is increased in C. elegans models of Huntington's disease but does not contribute to polyglutamine toxicity phenotypes.
abstract: Huntington's disease (HD) is an adult onset neurodegenerative disorder for which there is currently no cure. While HD patients and animal models of the disease exhibit increased oxidative damage, it is currently uncertain to what extent oxidative stress contributes to disease pathogenesis. In this work, we use a genetic approach to define the role of oxidative stress in HD. We find that a C. elegans model of HD expressing a disease-length polyglutamine tract in the body wall muscle is hypersensitive to oxidative stress and shows an upregulation of antioxidant defense genes, indicating that the HD worm model has increased levels of oxidative stress. To determine whether this increase in oxidative stress contributes to the development of polyglutamine-toxicity phenotypes in this HD model, we examined the effect of deleting individual superoxide dismutase (sod) genes in the HD worm model. As predicted, we found that deletion of sod genes in the HD worm model resulted in a clear increase in sensitivity to oxidative stress. However, we found that increasing oxidative stress in the HD worm model did not exacerbate deficits caused by polyglutamine toxicity. We confirmed these observations in two worm models expressing disease-length polyglutamine tracts in neurons. Furthermore, we found that treatment with antioxidants failed to rescue movement deficits or decrease aggregation in HD worm models. Combined, this suggests that the increase in oxidative stress in worm models of HD does not contribute to the phenotypic deficits observed in these worms, and provides a possible explanation for the failure of antioxidants in HD clinical trials.
authors.affiliation: Laboratory of Aging and Neurodegenerative Disease, Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Machiela
authors.affiliation: Laboratory of Aging and Neurodegenerative Disease, Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Dylan J
authors.initials: DJ
authors.lastname: Dues
authors.affiliation: Laboratory of Aging and Neurodegenerative Disease, Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Senchuk
authors.affiliation: Laboratory of Aging and Neurodegenerative Disease, Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA; Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Department of Genetics, Michigan State University, East Lansing, MI, USA. Electronic address: jeremy.vanraamsdonk@vai.org.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Van Raamsdonk
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D000975:Antioxidants / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D047108:Embryonic Development / Q000187:drug effects / Q000235:genetics*; D005947:Glucose / Q000494:pharmacology; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D009068:Movement / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000235:genetics* / Q000633:toxicity; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
chemical_list: D000975:Antioxidants; D001426:Bacterial Proteins; D029742:Caenorhabditis elegans Proteins; D008164:Luminescent Proteins; D010455:Peptides; D012333:RNA, Messenger; C054562:yellow fluorescent protein, Bacteria; C097188:polyglutamine; D005947:Glucose
keywords: C. elegans; Huntington's disease; aggregation; animal model; genetics; oxidative stress; polyglutamine toxicity disorder; reactive oxygen species (ROS); superoxide dismutase