Résumé :
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Motor neuron diseases (MND) are rare diseases characterized by degeneration of lower (spinal muscular atrophy, SMA), upper (spastic paraplegia, HSP and primary lateral sclerosis) or both upper and lower motor neurons (amyotrophic lateral sclerosis, ALS). The identification of genes responsible for these diseases revealed two main pathways, RNA metabolism/translation and axonal transport. In addition, human genetic data suggest that MND share pathogenic molecular pathway(s). SMA linked to SMN1 mutations is a frequent lower MND. SMN facilitates the formation of the spliceosome complex. The pathway linking SMN defect to degeneration of motor neurons only remains unclear. The generation of human motor neuron cellular models would be very helpful to clarify the SMA pathogenesis. SMN1 is duplicated in a homologous gene called SMN2 which remains present in patients. Upregulation of the SMN2 gene expression or preventing exon 7 skipping of SMN2 transcripts have been selected as therapeutic strategies in SMA. Improving the stability of the SMN?7 protein, the major product of SMN2, may be also regarded as a new attractive one. Alternatively or in combination with the above strategy, neuroprotective or neurotrophic factors may protect neurons from degeneration. Several compounds have been identified and are good candidates for clinical trials in human SMA. Mutations of the spastin gene (Sp) are responsible for the most frequent autosomal dominant form of HSP. Spastin in involved in microtubule dynamics. Spastin knock out mice display progressive axonal degeneration characterized by focal axonal swellings associated with focal impairment of retrograde transport. These defects occur in a region of axon characterized by the transition between stable and dynamic microtubules which highlights the link between spastin, microtubule dynamics and axonal transport. Compounds acting on the microtubule dynamics should be regarded as good candidates to act on the defective axonal transport mediated by the spastin mutation.
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