NPGPx-Mediated Adaptation to Oxidative Stress Protects Motor Neurons from Degeneration in Aging by Directly Modulating O-GlcNAcase
Journal
Cell Reports
Journal Volume
29
Journal Issue
8
Pages
2134-2143.e7
Date Issued
2019
Author(s)
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)
Subjects
aging; ALS; motor neuron; NPGPx; O-GlcNAcylation; OGA; oxidative stress
SDGs
Other Subjects
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
Type
journal article