System xC− is a mediator of microglial function and its deletion slows symptoms in amyotrophic lateral sclerosis mice - CEA - Commissariat à l’énergie atomique et aux énergies alternatives Accéder directement au contenu
Article Dans Une Revue Brain - A Journal of Neurology Année : 2015

System xC− is a mediator of microglial function and its deletion slows symptoms in amyotrophic lateral sclerosis mice

Résumé

Amyotrophic lateral sclerosis is the most common adult-onset motor neuron disease and evidence from mice expressing amyo-trophic lateral sclerosis-causing SOD1 mutations suggest that neurodegeneration is a non-cell autonomous process where microglialcells influence disease progression. However, microglial-derived neurotoxic factors still remain largely unidentified in amyotrophiclateral sclerosis. With excitotoxicity being a major mechanism proposed to cause motor neuron death in amyotrophic lateralsclerosis, our hypothesis was that excessive glutamate release by activated microglia through their system xC(a cystine/glutamateantiporter with the specific subunit xCT/Slc7a11) could contribute to neurodegeneration. Here we show that xCT expression isenriched in microglia compared to total mouse spinal cord and absent from motor neurons. Activated microglia induced xCTexpression and during disease, xCT levels were increased in both spinal cord and isolated microglia from mutant SOD1 amyo-trophic lateral sclerosis mice. Expression of xCT was also detectable in spinal cord post-mortem tissues of patients with amyo-trophic lateral sclerosis and correlated with increased inflammation. Genetic deletion of xCT in mice demonstrated that activatedmicroglia released glutamate mainly through system xC. Interestingly, xCT deletion also led to decreased production of specificmicroglial pro-inflammatory/neurotoxic factors including nitric oxide, TNFa and IL6, whereas expression of anti-inflammatory/neuroprotective markers such as Ym1/Chil3were increased, indicating that xCT regulates microglial functions. In amyotrophiclateral sclerosis mice, xCT deletion surprisingly led to earlier symptom onset but, importantly, this was followed by a significantlyslowed progressive disease phase, which resulted in more surviving motor neurons. These results are consistent with a deleteriouscontribution of microglial-derived glutamate during symptomatic disease. Therefore, we show that system xCparticipates inmicroglial reactivity and modulates amyotrophic lateral sclerosis motor neuron degeneration, revealing system xCinactivation,as a potential approach to slow amyotrophic lateral sclerosis disease progression after onset of clinical symptoms.

Domaines

Neurobiologie
Fichier principal
Vignette du fichier
mesci-brain-2015.pdf (1.57 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)
Loading...

Dates et versions

cea-02168384 , version 1 (28-06-2019)

Identifiants

Citer

Pinar Mesci, Sakina Zaïdi, Christian S. Lobsiger, Stéphanie Millecamps, Carole Escartin, et al.. System xC− is a mediator of microglial function and its deletion slows symptoms in amyotrophic lateral sclerosis mice. Brain - A Journal of Neurology , 2015, 138 (1), pp.53-68. ⟨10.1093/brain/awu312⟩. ⟨cea-02168384⟩
38 Consultations
91 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More