The motor neuron disease spinal muscular atrophy (SMA) results from mutations that lead to low levels of the ubiquitously expressed protein survival of motor neuron (SMN). An ever-increasing collection of data suggests that therapeutics that elevate SMN may be effective in treating SMA. We executed an image-based screen of annotated chemical libraries and discovered several classes of compounds that were able to increase cellular SMN. Among the most important was the RTK–PI3K–AKT–GSK-3 signaling cascade. Chemical inhibitors of glycogen synthase kinase 3 (GSK-3) and short hairpin RNAs (shRNAs) directed against this target elevated SMN levels primarily by stabilizing the protein. It was particularly notable that GSK-3 chemical inhibitors were also effective in motor neurons, not only in elevating SMN levels, but also in blocking the death that was produced when SMN was acutely reduced by an SMN-specific shRNA. Thus, we have established a screen capable of detecting drug-like compounds that correct the main phenotypic change underlying SMA.
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The authors would like to thank K. Kotkow, Y. M. Yang and K. Chen for helpful comments, K. Krumholz for technical help and J. LaLonde for editorial assistance. Additionally, we would like to thank R. Sivasankaran and C. Song at Novartis for sharing the conditions of the splicing assay design. The work was supported by the Spinal Muscular Atrophy Foundation, by the Harvard Stem Cell Institute and by a P01 grant (P01NS066888-01A1) from the US National Institute of Neurological Disorders and Stroke (NINDS). Mouse Hb9∷CFP was a gift from K. Eggan, Harvard University.
L.L.R. is a founder of iPierian and a member of its Scientific Advisory Board.
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