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

doi:10.1016/j.celrep.2019.10.053

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease (MND) and is characterized clinically by muscle wasting, leading to respiratory failure and subsequent death (Taylor et al, 2016)
We report that changes in NPGPxmediated O-GlcNAcylation orchestrated by modulation of OGA activity act as an adaptive mechanism to cope with chronic oxidative-stress-targeting motor neuron (MN) degeneration in aging animals
10% of NPGPx KO mice at about 1 year old developed severe MND-related features, such as hindlimb paralysis, abnormal hindlimb clasping, and muscle wasting (Figure 1A). These KO mice lost choline acetyltransferase (ChAT)-positive MNs in their spinal cords (SCs) (Figure S1A) accompanied by neuromuscular junction (NMJ) denervation in their gastrocnemius muscles (Figure S1B). This suggested that the paralysis occurring in these KO mice was due to MN degeneration

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease (MND) and is characterized clinically by muscle wasting, leading to respiratory failure and subsequent death (Taylor et al, 2016). ALS has no effective treatment, as the underlying etiological mechanism(s) remain unclear. About 90% of ALS cases are sporadic and thought to result from interactions between factors that include individual genetic predisposition, environment, and aging (Riancho et al, 2019). Aging is the most common risk factor for ALS (Mayeux, 2003) and is associated with elevated oxidative stress and cell injury. The degree of oxidative stress in aerobic organisms shifts with changes in environment, metabolism, lifestyle, and age. Aerobic organisms develop several protective mechanisms to cope with oxidative stress. Whether NPGPx is involved in the ALS pathogenesis remains unexplored

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