Résumé :
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Communication n° 674 Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of motoneurons in the cortex, brainstem and spinal cord. It is widely accepted that motoneurons die by apoptotic mechanisms but the initiating events are still poorly understood. Our recent data showed that a specific Histone Acetyl Transferase (HAT), namely the CREB-Binding Protein (CBP) disappears in motoneurons from the lumbar spinal cord of an in vivo mouse model of ALS (SOD1 G86R mice) when compared to those of wild type animals. We also found decreased levels of acetylated histones in these motoneurons. The aim of this study was to investigate whether preventing the loss of acetylation by blocking histone deacetylation with specific inhibitors (HDACIs) could have an impact on motoneuronal death. We used a cellular model of motoneurons (the NSC34 neuroblastoma X Spinal cord cell line) in which oxidative stress, and subsequent death, was induced by a pulse of hydrogen peroxide. First of all, we found that, as observed in degenerating motoneurons of SOD1 G86R mice, H2O2-induced motorneuronal death was accompanied by CBP loss and a subsequent decrease in histone H3 acetylation. We then tested several HDACIs: Trichostatin A (TSA), Valproic acid, (VPA) and Sodium Butyrate (NaBu) and found that all compounds prevented H2O2-induced neuronal apoptosis, to a different extend. TSA was the more potent molecule that could reverse motoneuronal death, at doses that were also able to re-establish similar acetylation levels than those observed in the control situation. Taken together, these results are in favour of a beneficial effect of these molecules on motoneuronal death and we are currently investigating their potency as therapeutic tools in vivo, in the SOD G86R mouse strain.
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