NPGPx-Mediated Adaptation to Oxidative Stress Protects Motor Neurons from Degeneration in Aging by Directly Modulating O-GlcNAcase

Yung Lin Hsieh, Fang Yi Su, Li Kai Tsai, Chien Chang Huang, Yi Ling Ko, Li Wen Su, Kai Yun Chen, Hsiu Ming Shih, Chun Mei Hu, Wen Hwa Lee

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)2134-2143.e7
JournalCell Reports
Volume29
Issue number8
DOIs
Publication statusPublished - Nov 19 2019

Keywords

  • aging
  • ALS
  • motor neuron
  • NPGPx
  • O-GlcNAcylation
  • OGA
  • oxidative stress

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Hsieh, Y. L., Su, F. Y., Tsai, L. K., Huang, C. C., Ko, Y. L., Su, L. W., Chen, K. Y., Shih, H. M., Hu, C. M., & Lee, W. H. (2019). NPGPx-Mediated Adaptation to Oxidative Stress Protects Motor Neurons from Degeneration in Aging by Directly Modulating O-GlcNAcase. Cell Reports, 29(8), 2134-2143.e7. https://doi.org/10.1016/j.celrep.2019.10.053