Abstract
Most patients with the pediatric neurodegenerative disease spinal muscular atrophy have a homozygous deletion of the survival motor neuron 1 (SMN1) gene, but retain one or more copies of the closely related SMN2 gene. The SMN2 gene encodes the same protein (SMN) but produces it at a low efficiency compared with the SMN1 gene. We performed a high-throughput screen of approximately 47,000 compounds to identify those that increase production of an SMN2-luciferase reporter protein, but not an SMN1-luciferase reporter protein. Indoprofen, a nonsteroidal anti-inflammatory drug (NSAID) and cyclooxygenase (COX) inhibitor, selectively increased SMN2-luciferase reporter protein and endogenous SMN protein and caused a 5-fold increase in the number of nuclear gems in fibroblasts from SMA patients. No other NSAIDs or COX inhibitors tested exhibited this activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Cyclic AMP Response Element-Binding Protein
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Cyclooxygenase Inhibitors / pharmacology
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Drug Evaluation, Preclinical
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Female
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Fibroblasts / enzymology
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Humans
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Indoprofen / pharmacokinetics
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Indoprofen / pharmacology*
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Mice
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Nerve Tissue Proteins / biosynthesis*
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Nerve Tissue Proteins / genetics
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Pregnancy
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Prostaglandin-Endoperoxide Synthases / physiology
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RNA-Binding Proteins
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SMN Complex Proteins
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Survival of Motor Neuron 1 Protein
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Survival of Motor Neuron 2 Protein
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Up-Regulation
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Cyclic AMP Response Element-Binding Protein
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Cyclooxygenase Inhibitors
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Nerve Tissue Proteins
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RNA-Binding Proteins
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SMN Complex Proteins
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SMN1 protein, human
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SMN2 protein, human
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Smn1 protein, mouse
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Survival of Motor Neuron 1 Protein
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Survival of Motor Neuron 2 Protein
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Indoprofen
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Prostaglandin-Endoperoxide Synthases