Regulation of system xc - in the SOD1-G93A mouse model of ALS

The cystine/glutamate antiporter (system x(c)-) is critical for the generation of the antioxidant glutathione by transporting cystine into the cell. At the same time, system x(c)- also releases glutamate, which can potentially lead to excitotoxicity. The dual actions of system x(c)- make it of great interest in any disease, like amyotrophic lateral sclerosis (ALS), in which there is evidence of the involvement of both oxidative stress and excitotoxicity. The present study investigated the regulation of system x(c)- in the spinal cord of the SOD1-G93A transgenic mouse model of ALS. In acute spinal cord slices of 70 day old SOD1-G93A transgenic mice cystine uptake by system x(c)- was significantly increased compared to age matched non-transgenic mice; but it was not significantly different at 55,100, or 130 days. The 70 day old SOD1-G93A transgenic mice also showed significantly increased glutamate release in the presence of cystine. D-Aspartate uptake through excitatory amino acid transporters (EAATs), the main mechanism by which glutamate is cleared from the extracellular space, was also examined. In spinal cord slices of 70 day old SOD1-G93A mice no change in D-aspartate uptake was found. Together, these findings suggest that at 70 days of age, SOD1-G93A transgenic mice have increased system x(c)- activity, but no change in EAAT function. These results raise the possibility that excitotoxicity in the SOD1-G93A transgenic mouse, at least at early time points, may be due to increased system x(c)- activity and not decreased EAAT function. (C) 2013 Elsevier Inc. All rights reserved.