Oxr1 Is Essential for Protection against Oxidative Stress-Induced Neurodegeneration

Oxidative stress is a common etiological feature of neurological disorders, although the pathways that govern defence against reactive oxygen species (ROS) in neurodegeneration remain unclear. We have identified the role of oxidation resistance 1 (Oxr1) as a vital protein that controls the sensitivity of neuronal cells to oxidative stress; mice lacking Oxr1 display cerebellar neurodegeneration, and neurons are less susceptible to exogenous stress when the gene is over-expressed. A conserved short isoform of Oxr1 is also sufficient to confer this neuroprotective property both in vitro and in vivo. In addition, biochemical assays indicate that Oxr1 itself is susceptible to cysteine-mediated oxidation. Finally we show up-regulation of Oxr1 in both human and pre-symptomatic mouse models of amyotrophic lateral sclerosis, indicating that Oxr1 is potentially a novel neuroprotective factor in neurodegenerative disease.

Author Summary Oxygen is vital for life, but it can also cause damage to cells. Consequently, protective proteins (antioxidants) are utilised to maintain the fine balance between oxygen metabolism and the production of potentially toxic reactive oxygen species (ROS). If this balance is not maintained, oxidative stress occurs and excess ROS are generated, causing damage to DNA, proteins, and lipids. The brain is particularly susceptible to oxidative stress, and ROS–induced damage is a common feature of all major neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). However, the molecular mechanisms of ROS defence in neurons are still under investigation. Here we describe the characterisation of oxidation resistance 1 (Oxr1), a gene previously shown to be induced under oxidative stress. We show both in mice and in cells that loss of Oxr1 causes cell death and that increasing protein levels can protect against ROS. In addition, Oxr1 is over-expressed in the spinal cord in ALS patients, as well as in a pre-symptomatic ALS mouse model. These data demonstrate for the first time that Oxr1 is vital for the protection of neuronal cells against oxidative stress and that induction of Oxr1 may be relevant to neurodegenerative pathways in disease.