System xc- or the cystine/glutamate antiporter is responsible for exchanging intracellular glutamate for extracellular cystine. Cystine is intracellularly reduced to cysteine, the rate-limiting building block in the synthesis of glutathione. As such, malfunctioning of system xc- can cause oxidative stress as well as excitotoxicity (due to elevated glutamate levels). Both phenomena are common mechanisms in neurological disorders, including multiple sclerosis (MS). To explore the contribution of system xc- to the pathogenesis of MS, we investigated on one hand xCT (specific subunit of system xc-) expression in mouse models for MS as well as brain samples of MS patients, and on the other hand we studied the effect of genetic deletion of xCT on the outcome of mice in the EAE (experimental autoimmune encephalomyelitis) mouse model for MS. No changes in xCT expression were observed in the brain and spinal cord of the TMEV (Theiler’s murine encephalomyelitis virus) mouse model for MS. On the other hand, xCT protein expression was significantly increased in brain, spinal cord and spleen samples of EAE mice as well as in normal appearing white matter of MS patients compared to healthy control subjects. Whereas EAE induction in xCT-/- mice (genetic deletion of xCT and as such deficiency for system xc-) resulted in a slightly more severe clinical outcome compared to xCT+/+ littermates, the loss of system xc- in immune cells (after xCT-/- bone marrow transplantation to irradiated mice), resulted in a moderate, but significant, protection in the EAE model compared to their proper controls (xCT+/+ bone marrow transplantation to irradiated mice). Our findings confirm the involvement of system xc- in the pathogenesis of MS and suggest a pathological contribution of enhanced system xc- on immune cells infiltrating the central nervous system.
|Title of host publication||45th Annual Meeting of the Society for Neuroscience, 17-21 Oktober 2015, Chicago, USA|
|Publication status||Published - 2015|
|Event||45th Annual Meeting of the Society for Neuroscience - Chicago, United States|
Duration: 17 Oct 2015 → 21 Oct 2015
|Conference||45th Annual Meeting of the Society for Neuroscience|
|Period||17/10/15 → 21/10/15|