A screen for regulators of survival of motor neuron protein levels.

Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101231976 Publication Model: Electronic Cited Medium: Internet ISSN: 1552-4469 (Electronic) Linking ISSN: 15524450 NLM ISO Abbreviation: Nat Chem Biol Subsets: MEDLINE

Original Publication: New York, NY : Nature Pub. Group, [2005]-

Drug Discovery/*methods ; Gene Expression Regulation/*drug effects ; Muscular Atrophy, Spinal/*drug therapy ; Survival of Motor Neuron 1 Protein/*metabolism; Adult ; Animals ; Benzazepines/pharmacology ; Cells, Cultured ; Child, Preschool ; Embryonic Stem Cells ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Gene Expression Regulation/physiology ; Gene Silencing ; Glycogen Synthase Kinase 3/antagonists & inhibitors ; Glycogen Synthase Kinase 3 beta ; Humans ; Indoles/pharmacology ; Mice ; Motor Neurons/metabolism ; Muscular Atrophy, Spinal/metabolism ; Mutation ; Platelet-Derived Growth Factor/pharmacology ; STAT1 Transcription Factor ; Small Molecule Libraries ; Survival of Motor Neuron 1 Protein/genetics ; Survival of Motor Neuron 2 Protein/genetics ; Survival of Motor Neuron 2 Protein/metabolism

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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P01 NS066888 United States NS NINDS NIH HHS; P01 NS066888-01A1 United States NS NINDS NIH HHS; P01NS066888-01A1 United States NS NINDS NIH HHS

0 (Benzazepines)
0 (Indoles)
0 (Platelet-Derived Growth Factor)
0 (SMN1 protein, human)
0 (SMN2 protein, human)
0 (STAT1 Transcription Factor)
0 (Small Molecule Libraries)
0 (Survival of Motor Neuron 1 Protein)
0 (Survival of Motor Neuron 2 Protein)
0 (alsterpaullone)
EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
EC 2.7.11.26 (Glycogen Synthase Kinase 3)

Date Created: 20110621 Date Completed: 20110929 Latest Revision: 20211020

20221213

PMC3236614

10.1038/nchembio.595

21685895