| First Author | Hsieh YL | Year | 2019 |
| Journal | Cell Rep | Volume | 29 |
| Issue | 8 | Pages | 2134-2143.e7 |
| PubMed ID | 31747588 | Mgi Jnum | J:300797 |
| Mgi Id | MGI:6488949 | Doi | 10.1016/j.celrep.2019.10.053 |
| Citation | Hsieh YL, et al. (2019) NPGPx-Mediated Adaptation to Oxidative Stress Protects Motor Neurons from Degeneration in Aging by Directly Modulating O-GlcNAcase. Cell Rep 29(8):2134-2143.e7 |
| abstractText | 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. |
