Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis.

Kevin X Liu,Ben Davies,Mattéa J Finelli,Kay E Davies,Peter L Oliver,Benjamin Edwards,Sheena Lee

doi:10.1093/brain/awv039

Abstract

Amyotrophic lateral sclerosis is a devastating neurodegenerative disorder characterized by the progressive loss of spinal motor neurons. While the aetiological mechanisms underlying the disease remain poorly understood, oxidative stress is a central component of amyotrophic lateral sclerosis and contributes to motor neuron injury. Recently, oxidation resistance 1 (OXR1) has emerged as a critical regulator of neuronal survival in response to oxidative stress, and is upregulated in the spinal cord of patients with amyotrophic lateral sclerosis. Here, we tested the hypothesis that OXR1 is a key neuroprotective factor during amyotrophic lateral sclerosis pathogenesis by crossing a new transgenic mouse line that overexpresses OXR1 in neurons with the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Interestingly, we report that overexpression of OXR1 significantly extends survival, improves motor deficits, and delays pathology in the spinal cord and in muscles of SOD1(G93A) mice. Furthermore, we find that overexpression of OXR1 in neurons significantly delays non-cell-autonomous neuroinflammatory response, classic complement system activation, and STAT3 activation through transcriptomic analysis of spinal cords of SOD1(G93A) mice. Taken together, these data identify OXR1 as the first neuron-specific antioxidant modulator of pathogenesis and disease progression in SOD1-mediated amyotrophic lateral sclerosis, and suggest that OXR1 may serve as a novel target for future therapeutic strategies.

Highlights

The neurodegenerative disorder amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper motor neurons in the cortex, and lower motor neurons in the brainstem and the spinal cord, resulting in severe muscle wasting and death due to respiratory failure (Hardiman et al, 2011)
First we confirmed that expression of HA-tagged oxidation resistance 1 (OXR1) protein occurs in the spinal cord and brain (Supplementary Fig. 1C); in addition, the oxidation resistance 1 (Oxr1) transgene is overexpressed as early as embryonic Day 13.5 (Fig. 1A and Supplementary Fig. 1D) and adult transgenic Tg(Prnp-Oxr1) mice show a consistent 5-fold increase in OXR1 protein expression compared to wild-type controls in the spinal cord (Fig. 1B) and brain (Supplementary Fig. 1E)
Immunohistochemistry confirmed the neuron-specific overexpression of OXR1; all Tg(PrnpOxr1) neurons express cytoplasmic HA-tagged OXR1, and no HA-stained cells are found in any NeuN-negative cell populations in the brain or spinal cord (Fig. 1C and Supplementary Fig. 1F)

Summary

Introduction

The neurodegenerative disorder amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper motor neurons in the cortex, and lower motor neurons in the brainstem and the spinal cord, resulting in severe muscle wasting and death due to respiratory failure (Hardiman et al, 2011). While most ALS cases are sporadic, $10% of cases are familial with mutations in Cu/Zn super oxide dismutase (SOD1) accounting for 20% of Received September 12, 2014.

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