國家衛生研究院 NHRI:Item 3990099045/12296
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    題名: NPGPx-mediated adaptation to oxidative stress protects motor neurons from degeneration in aging by directly modulating O-GlcNAcase
    作者: Hsieh, YL;Su, FY;Tsai, LK;Huang, CC;Ko, YL;Su, LW;Chen, KY;Shih, HM;Hu, CM;Lee, WH
    貢獻者: Institute of Molecular and Genomic Medicine
    摘要: 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.
    日期: 2019-11
    關聯: Cell Reports. 2019 Nov;29(8):2134-2143.
    Link to: http://dx.doi.org/10.1016/j.celrep.2019.10.053
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2211-1247&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000497954200003
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85074993516
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