Résumé :
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The SMN complex, comprised of the survival of motor neurons (SMN) protein and the Gemins, plays a central role in cellular RNA metabolism. The SMN complex is essential in all cells and functions as a molecular assembly machine for the biogenesis of small nuclear ribonucleoproteins (snRNPs, the major components of the cell’s mRNA splicing machinery) and likely other RNPs. Deficiency in functional SMN protein causes the motor neurons degenerative disease, spinal muscular atrophy (SMA). To study the molecular mechanism and regulation of the SMN complex, we developed a sensitive and quantitative activity assay for snRNP assembly. This revealed a measurable biochemical deficit in the capacity of SMA patient cells to form snRNPs, which corresponds directly to their SMN protein deficiency. Future progress towards finding a therapy for SMA will likely come from detailed understanding of the function, expression and regulation of the SMN complex, and from direct screens for modifiers of these processes. In practical terms, several therapeutic approaches can be envisioned for SMA. We developed assays and performed screens for small molecules based on two approaches in particular, 1) Compounds that increase the amount of SMN in SMA patient cells, and 2) Compounds that increase or bypass the activity of the SMN complex. Progress on large-scale screens, the activity of select compounds, and insights gained from them into the regulation of the SMN complex will be described.
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