Résumé :
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Spinal muscular atrophy (SMA) is characterized by a mutation in the survival motor neuron (SMN) gene, leading to a deficit of expression of the SMN protein, a ubiquitously expressed protein which exact function is unknown. It results in motoneuron degeneration and muscle atrophy. For a long time, SMA was considered as a motor neuron disease only, but recent findings involve the muscle in the development of the pathology, as well. We showed that a key regulator of muscle plasticity, the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1?), is able to protect muscle from disuse-induced atrophy and to regulate the expression of post-synaptic genes in the neuromuscular junction (NMJ). Many properties of PGC-1???as well as its beneficial effects on dystrophic phenotype in mdx mice, suggest that it might be a potential therapeutic target in SMA.For this study, we have three different transgenic mice: SMA models (SMA I and SMA III) and a PGC-1? global KO mouse. The expression of PGC-1?, SMN and other RNA metabolism genes assessed by real-time PCR, and the expression of specific markers for the NMJ (acetylcholine receptors, neurofilaments, synaptophysin...) observed by immunohistochemistry showed differences between those models. These experiments give insights into the possible mechanistic links between PGC-1? and SMN at the muscle and the NMJ levels. We have at our disposal different constructs allowing us to over-or under-express either SMN or PGC-1? in primary muscle cells coming from our models. By using different combinations of those constructs, followed by the innervations of the cells with rat spinal cords explants, we can observe the behavior of the nerve-muscle cocultures and highlight the possible beneficial effect of PGC-1? on the SMA phenotype Those preliminary results will open the way for a brand new field in the treatment of SMA, a devastating disease for which therapeutic breakthrough are desperately needed.
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