title: Regulation of system x(c)- in the SOD1-G93A mouse model of ALS.
abstract: The cystine/glutamate antiporter (system xc-) is critical for the generation of the antioxidant glutathione by transporting cystine into the cell. At the same time, system xc- also releases glutamate, which can potentially lead to excitotoxicity. The dual actions of system xc- 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 xc- in the spinal cord of the SOD1-G93A transgenic mouse model of ALS. In acute spinal cord slices of 70day old SOD1-G93A transgenic mice cystine uptake by system xc- was significantly increased compared to age matched non-transgenic mice; but it was not significantly different at 55, 100, or 130days. The 70day 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 70day old SOD1-G93A mice no change in d-aspartate uptake was found. Together, these findings suggest that at 70days of age, SOD1-G93A transgenic mice have increased system xc- 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 xc- activity and not decreased EAAT function.
authors.affiliation: Dept. of Biomedical Sciences, Marquette University, 561 N. 15th Street, Rm 426, Milwaukee, WI 53233, USA. Electronic address: rebecca.albano@marquette.edu.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Albano
authors.forename: XiaoQian
authors.initials: X
authors.lastname: Liu
authors.forename: Doug
authors.initials: D
authors.lastname: Lobner
mesh_terms: D026922:Amino Acid Transport Systems, Acidic / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D027341:Excitatory Amino Acid Transporter 1; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013116:Spinal Cord / Q000378:metabolism*
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D027341:Excitatory Amino Acid Transporter 1
keywords: ALS; Amyotrophic lateral sclerosis; Cystine; DL-threo-β-benzyloxyaspartic acid; EAAT; Excitotoxicity; GLT-1; Glutamate; Oxidative stress; SOD-1; SSZ; System x(c)−; TBOA; amyotrophic lateral sclerosis; excitatory amino acid transporter; glial glutamate transporter 1; sulfasalazine; superoxide dismutase 1