Résumé :
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Communication n° 455 Spinal muscular atrophy (SMA) is caused by mutations in the gene encoding the survival motor neuron (SMN) protein, SMN1. The SMN1 gene and its nearly identical copy SMN2 produce an identical ubiquitous SMN protein. A strong correlation exists between the severity of SMA disease and the reduction of SMN protein levels and of gems/Cajal bodies (CB) numbers. At present, there is no treatment for SMA, therefore, one potential therapeutic approach is to increase the SMN protein levels and numbers of CB to reduce or stop the progression of disease. Using immunoblot analyses of control and SMA-derived cell cultures, we have shown that SMN protein levels are increased following either interleukin-6 (IL-6) or all trans retinoic acid (RA) treatment. Immunofluorescence studies reveal that in IL-6 treated SMA type I fibroblasts the number of cells with gems/CB is markedly increased to 23% compared to 6% of cells with gems/CB in untreated SMA cell cultures. In IL-6-treated control fibroblasts there are 95% of cells with gems/CB compared to 78% in untreated control cells. Under RA treatments the number of control fibroblasts with CB is severely reduced to 23% compared to untreated cells and there is no gems/CB in RA-treated SMA fibroblasts. Interestingly, while both molecules augment the SMN protein levels, they show opposite effect on the localization of SMN in CB. In IL-6 treated SMA cell cultures the SMN protein accumulates in CB, whereas in RA-treated SMA cell cultures the protein remains in the nucleoplasm. Furthermore, SMN2 quantitative real-time RT-PCR does not show an increase in SMN transcripts under IL-6 treatment. These results indicate that IL-6 may translationally regulate the SMN protein expression and reveal a novel mechanism by which SMN expression can be upregulated as an additional putative therapeutic strategy. Finally, the ongoing screens of additional compounds will be discussed.
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