Machiela Emily, Dues Dylan J, Senchuk Megan M, Van Raamsdonk Jeremy M
Laboratory of Aging and Neurodegenerative Disease, Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.
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.
Neurobiol Dis. 2016 Dec;96:1-11. doi: 10.1016/j.nbd.2016.08.008. Epub 2016 Aug 18.
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.
亨廷顿舞蹈症（HD）是一种成年发病的神经退行性疾病，目前尚无治愈方法。虽然HD患者及该疾病的动物模型表现出氧化损伤增加，但目前尚不清楚氧化应激在多大程度上促成疾病发病机制。在这项研究中，我们采用遗传学方法来确定氧化应激在HD中的作用。我们发现，在体壁肌肉中表达疾病长度多聚谷氨酰胺序列的HD秀丽隐杆线虫模型对氧化应激高度敏感，且抗氧化防御基因上调，这表明HD线虫模型的氧化应激水平升高。为了确定这种氧化应激增加是否促成该HD模型中多聚谷氨酰胺毒性表型的发展，我们检测了在HD线虫模型中删除单个超氧化物歧化酶（sod）基因的效果。正如预期的那样，我们发现在HD线虫模型中删除sod基因导致对氧化应激的敏感性明显增加。然而，我们发现增加HD线虫模型中的氧化应激并不会加剧多聚谷氨酰胺毒性引起的缺陷。我们在两个在神经元中表达疾病长度多聚谷氨酰胺序列的线虫模型中证实了这些观察结果。此外，我们发现用抗氧化剂治疗无法挽救HD线虫模型中的运动缺陷或减少聚集。综合来看，这表明HD线虫模型中氧化应激的增加不会导致这些线虫中观察到的表型缺陷，并为HD临床试验中抗氧化剂的失败提供了一种可能的解释。
