Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug‐like compounds
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 f...
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| Format: | Article |
| Language: | English |
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Springer Nature
2013-06-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1002/emmm.201202305 |
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| author | Jonathan J. Cherry Erkan Y. Osman Matthew C. Evans Sungwoon Choi Xuechao Xing Gregory D. Cuny Marcie A. Glicksman Christian L. Lorson Elliot J. Androphy |
| author_facet | Jonathan J. Cherry Erkan Y. Osman Matthew C. Evans Sungwoon Choi Xuechao Xing Gregory D. Cuny Marcie A. Glicksman Christian L. Lorson Elliot J. Androphy |
| author_sort | Jonathan J. Cherry |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d87b1837bfc644f1a80827699a5c93bc |
| institution | OA Journals |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2013-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-d87b1837bfc644f1a80827699a5c93bc2025-08-20T02:18:33ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842013-06-01571103111810.1002/emmm.201202305Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug‐like compoundsJonathan J. Cherry0Erkan Y. Osman1Matthew C. Evans2Sungwoon Choi3Xuechao Xing4Gregory D. Cuny5Marcie A. Glicksman6Christian L. Lorson7Elliot J. Androphy8Department of Medicine, University of Massachusetts Medical SchoolDepartment of Veterinary Pathobiology, Bond Life Sciences Center, University of MissouriDerpartment of Dermatology, Indiana University School of MedicineLaboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital and Harvard Medical SchoolLaboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital and Harvard Medical SchoolLaboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital and Harvard Medical SchoolLaboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women's Hospital and Harvard Medical SchoolDepartment of Veterinary Pathobiology, Bond Life Sciences Center, University of MissouriDepartment of Medicine, University of Massachusetts Medical SchoolAbstract 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.https://doi.org/10.1002/emmm.201202305drug discoverySMASMNSMN2spinal muscular atrophy |
| spellingShingle | Jonathan J. Cherry Erkan Y. Osman Matthew C. Evans Sungwoon Choi Xuechao Xing Gregory D. Cuny Marcie A. Glicksman Christian L. Lorson Elliot J. Androphy Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug‐like compounds EMBO Molecular Medicine drug discovery SMA SMN SMN2 spinal muscular atrophy |
| title | Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug‐like compounds |
| title_full | Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug‐like compounds |
| title_fullStr | Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug‐like compounds |
| title_full_unstemmed | Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug‐like compounds |
| title_short | Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug‐like compounds |
| title_sort | enhancement of smn protein levels in a mouse model of spinal muscular atrophy using novel drug like compounds |
| topic | drug discovery SMA SMN SMN2 spinal muscular atrophy |
| url | https://doi.org/10.1002/emmm.201202305 |
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