Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Benzazepines / pharmacology
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Cells, Cultured
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Child, Preschool
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Drug Discovery / methods*
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Embryonic Stem Cells
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / physiology
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Gene Silencing
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Glycogen Synthase Kinase 3 beta
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Humans
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Indoles / pharmacology
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Mice
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Motor Neurons / metabolism
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Muscular Atrophy, Spinal / drug therapy*
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Muscular Atrophy, Spinal / metabolism
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Mutation
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Platelet-Derived Growth Factor / pharmacology
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STAT1 Transcription Factor
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Small Molecule Libraries
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Survival of Motor Neuron 1 Protein / genetics
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Survival of Motor Neuron 1 Protein / metabolism*
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Survival of Motor Neuron 2 Protein / genetics
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Survival of Motor Neuron 2 Protein / metabolism
Substances
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Benzazepines
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Indoles
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Platelet-Derived Growth Factor
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SMN1 protein, human
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SMN2 protein, human
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STAT1 Transcription Factor
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Small Molecule Libraries
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Survival of Motor Neuron 1 Protein
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Survival of Motor Neuron 2 Protein
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alsterpaullone
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3