Following the project selected in 2009 by the Thierry Latran Foundation : Study of the pathological neuro-immune interactions between the macrophages/microglial cells and the affected motor neurons in animal models of ALS ( PI Séverine Boillée, Sorbonne Universités, UPMC Univ Paris06, INSERM U1127, CNRS UMR 7225, ICM: Brain and Spinal Cord Institute, Hôpital de la Pitié-Salpêtrière,Paris)
Severine Boillée presents for the Foundation the results of her study just published in Brain:
“System xC- is a mediator of microglial function and its deletion slows symptoms in amyotrophic lateral sclerosis” Mesci P, Zaïdi S, Lobsiger CS, Millecamps S, Escartin C, Seilhean D, Sato H, Mallat M, Boillée S.
Previous work including from our own team has shown that microglial cells, the macrophages (immune cells) of the central nervous system, are implicated in ALS disease progression in mouse models. Microglial cells become activated over the course of the disease and this activation can result in the production of both trophic but also deleterious neurotoxic factors, which could harm affected motor neurons.
However, such toxic microglial factors implicated in motor neuron degeneration in ALS remain largely unknown. Since microglial cells are implicated in the progression of the disease, blocking microglial toxic factors could help slow down ALS disease progression, which would be relevant for the majority of ALS patients.
With this project, funded by the Thierry Latran foundation, we wanted to analyze the implication of “system xc-“ in ALS. System xc- is a transporter that allows cells to release glutamate. Since increasing extracellular glutamate levels is linked to so-called “excitotoxicity”, and such excitotoxicity is one of the major hypothesis to explain motor neuron degeneration in ALS, we wondered if system xc- could be a microglial target implicated in motor neuron degeneration in ALS.
First, using both culture and animal models, we showed that microglial cells expressed system xc- and to a higher level when they were activated. In ALS mouse models, system xc- was overexpressed in the spinal cord and in activated microglial cells during the disease. In addition, we showed that system xc- was expressed in human ALS spinal cord post-mortem tissues and its expression levels were correlated with the amount of microglial activation.
Second, using gene knock-out mice where system xc- was deleted, we analyzed the implication of this transporter on microglial cell functions. We showed that microglial cells, deprived of system xc-, released 70% less glutamate. In addition, system xc- was also implicated in the production of other microglial toxic factors including nitric oxide (NO) and TNF-alpha.
Therefore, we showed that system xc- participated in neurotoxic microglial cell functions, which means that blocking system xc- could be a target to decrease activated microglial cell toxicity. Indeed, we showed that deleting system xc- in ALS mice had an impact on microglial cells, since during the symptomatic phase they expressed more markers linked to a neurotrophic (less neurotoxic) response. Deleting system xc- in ALS mice increased the duration of this symptomatic disease phase.
Therefore, blocking system xc- with specific blockers during the symptomatic disease phase could be an approach to slow down ALS disease progression and increase lifespan.
However, this still remains to be done in ALS mice as available system xc- specific blockers are lacking specificity. Therefore, development of better system xc- blockers could be an interesting prospect to target a defined deleterious pathway implicated in ALS disease progression.