https://scholars.lib.ntu.edu.tw/handle/123456789/587967
Title: | NPGPx-Mediated Adaptation to Oxidative Stress Protects Motor Neurons from Degeneration in Aging by Directly Modulating O-GlcNAcase | Authors: | Hsieh Y.-L. Su F.-Y. LI-KAI TSAI Huang C.-C. Ko Y.-L. Su L.-W. Chen K.-Y. Shih H.-M. Hu C.-M. Lee W.-H. |
Keywords: | aging; ALS; motor neuron; NPGPx; O-GlcNAcylation; OGA; oxidative stress | Issue Date: | 2019 | Journal Volume: | 29 | Journal Issue: | 8 | Start page/Pages: | 2134-2143.e7 | Source: | Cell Reports | Abstract: | Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, usually occurs in middle-aged people. However, the molecular basis of age-related cumulative stress in ALS pathogenesis remains elusive. Here, we found that mice deficient in NPGPx (GPx7), an oxidative stress sensor, develop ALS-like phenotypes, including paralysis, muscle denervation, and motor neurons loss. Unlike normal spinal motor neurons that exhibit elevated O-GlcNAcylation against age-dependent oxidative stress, NPGPx-deficient spinal motor neurons fail to boost O-GlcNAcylation and exacerbate ROS accumulation, leading to cell death. Mechanistically, stress-activated NPGPx inhibits O-GlcNAcase (OGA) through disulfide bonding to fine-tune global O-GlcNAcylation. Pharmacological inhibition of OGA rescues spinal motor neuron loss in aged NPGPx-deficient mice. Furthermore, expression of NPGPx in ALS patients is significantly lower than in unaffected adults. These results suggest that NPGPx modulates O-GlcNAcylation by inhibiting OGA to cope with age-dependent oxidative stress and protect motor neurons from degeneration, providing a potential therapeutic axis for ALS. Hsieh et al. uncover an adaptive mechanism mediated by NPGPx in modulating O-GlcNAcylation to cope with chronic oxidative stress in aging. Stress-activated NPGPx restrains OGA activity through disulfide bonding and elevates O-GlcNAcylation to protect motor neurons from degeneration. ? 2019 The Author(s) |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85074993516&doi=10.1016%2fj.celrep.2019.10.053&partnerID=40&md5=9a918ad466a0ac7de21d93f22b156a4e https://scholars.lib.ntu.edu.tw/handle/123456789/587967 |
ISSN: | 22111247 | DOI: | 10.1016/j.celrep.2019.10.053 | SDG/Keyword: | hydrolase; NPGPx protein; o GlcNAcase; phospholipid hydroperoxide glutathione peroxidase; reactive oxygen metabolite; unclassified drug; beta n acetylhexosaminidase; hexosaminidase C; acylation; adaptation; adult; aged; aging; amyotrophic lateral sclerosis; animal cell; animal experiment; animal model; Article; cell death; clinical article; controlled study; disulfide bond; enzyme inhibition; female; gene; gene expression; human; human cell; male; motoneuron; mouse; nerve cell degeneration; nonhuman; NPGPx gene; oxidative stress; priority journal; aging; amyotrophic lateral sclerosis; animal; genetics; metabolism; motoneuron; muscle denervation; mutant mouse strain; oxidative stress; paralysis; physiology; Aging; Amyotrophic Lateral Sclerosis; Animals; beta-N-Acetylhexosaminidases; Female; Humans; Mice; Mice, Mutant Strains; Motor Neurons; Muscle Denervation; Oxidative Stress; Paralysis |
Appears in Collections: | 醫學院附設醫院 (臺大醫院) |
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