University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Department of Medicine

Date

7-2013

Document Type

Article

Medical Subject Headings

Animals; Cells, Cultured; *Drug Discovery; Fibroblasts; High-Throughput Screening Assays; Humans; Mice; Muscular Atrophy, Spinal; RNA, Messenger; Small Molecule Libraries; Survival of Motor Neuron 1 Protein; Survival of Motor Neuron 2 Protein; Up-Regulation

Disciplines

Biochemistry | Molecular Biology | Nervous System Diseases

Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease that causes progressive muscle weakness, which primarily targets proximal muscles. About 95% of SMA cases are caused by the loss of both copies of the SMN1 gene. SMN2 is a nearly identical copy of SMN1, which expresses much less functional SMN protein. SMN2 is unable to fully compensate for the loss of SMN1 in motor neurons but does provide an excellent target for therapeutic intervention. Increased expression of functional full-length SMN protein from the endogenous SMN2 gene should lessen disease severity. We have developed and implemented a new high-throughput screening assay to identify small molecules that increase the expression of full-length SMN from a SMN2 reporter gene. Here, we characterize two novel compounds that increased SMN protein levels in both reporter cells and SMA fibroblasts and show that one increases lifespan, motor function, and SMN protein levels in a severe mouse model of SMA.

Rights and Permissions

Citation: Cherry JJ, Osman EY, Evans MC, Choi S, Xing X, Cuny GD, Glicksman MA, Lorson CL, Androphy EJ. Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds. EMBO Mol Med. 2013 Jul;5(7):1035-50. doi: 10.1002/emmm.201202305. Link to article on publisher's site

Comments

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Related Resources

Link to Article in PubMed

Keywords

SMA, SMN, SMN2, drug discovery, spinal muscular atrophy

PubMed ID

23740718

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