Makhortova NR, Hayhurst M, Cerqueira A, Sinor-Anderson AD, Zhao WN, Heiser PW, Arvanites AC, Davidow LS, Waldon ZO, Steen JA, Lam K, Ngo HD, Rubin LL. 2011. A screen for regulators of survival of motor neuron protein levels. Nature chemical biology. 7(8):544-52. Pubmed: 21685895 DOI:10.1038/nchembio.595


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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Lee Rubin investigates the key molecular mediators of different neurodegenerative diseases, with the ultimate goal of finding effective preclinical therapeutic candidates.

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