Résumé :
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Death pathways restricted to specific neuronal classes could explain the selectivity of neuronal loss in neurodegenerative diseases, such as the loss of motoneurons in amyothrophic lateral sclerosis (ALS). We previously showed that Fas-induced death of motoneurons involves a motoneuron-specific cell death pathway, which is exacerbated in motoneurons expressing ALS-linked mutated SOD11-2. Importantly, involvement of Fas death pathway in the pathogenesis has been described3. However, Fas death pathway may not be responsible for the loss of all motoneurons, suggesting that other death pathways might be implicated. LIGHT is a member of the tumor necrosis factor receptor superfamily, which upon binding to the herpes virus entry mediator (HVEM) and/or the lymphotoxin-ß receptor (LT-ßR) can trigger death program in tumor cells. We show that cultured motoneurons express both LT-ßR and HVEM, and that soluble recombinant LIGHT induces death of about 50% of motoneurons through a non-classical caspase-dependent pathway. LIGHT-promoted death appears to be selective of motoneurons, since striatal, cortical and hippocampal neurons are resistant to LIGHT killing effect. Strikingly, we showed that LIGHT is additive to FasL, indeed both ligands, added together induce death of about 70% of motoneurons. We are currently investigating the role of LIGHT in the pathogenesis of ALS in animal models and its potential as a therapeutic target 1. Raoul, C. et al. (1999). J Cell Biol 147, 1049-62 2. Raoul, C. et al. (2002). Neuron 35, 1063-87 3. Raoul, C. et al. (2006). Proc Natl Acad Sci USA 103, 6007-12.
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