Hua, Y., Liu, Y. H., Sahashi, K., Rigo, F., Bennett, C. F., Krainer, A. R. (January 2015) Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models. Genes Dev, 29 (3). pp. 288-297. ISSN 0890-9369
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Abstract
Survival of motor neuron (SMN) deficiency causes spinal muscular atrophy (SMA), but the pathogenesis mechanisms remain elusive. Restoring SMN in motor neurons only partially rescues SMA in mouse models, although it is thought to be therapeutically essential. Here, we address the relative importance of SMN restoration in the central nervous system (CNS) versus peripheral tissues in mouse models using a therapeutic splice-switching antisense oligonucleotide to restore SMN and a complementary decoy oligonucleotide to neutralize its effects in the CNS. Increasing SMN exclusively in peripheral tissues completely rescued necrosis in mild SMA mice and robustly extended survival in severe SMA mice, with significant improvements in vulnerable tissues and motor function. Our data demonstrate a critical role of peripheral pathology in the mortality of SMA mice and indicate that peripheral SMN restoration compensates for its deficiency in the CNS and preserves motor neurons. Thus, SMA is not a cell-autonomous defect of motor neurons in SMA mice.
| Item Type: | Paper |
|---|---|
| Subjects: | organism description > model organism organism description > animal > mammal > rodent > mouse diseases & disorders > congenital hereditary genetic diseases > spinal muscular atrophy bioinformatics > genomics and proteomics > genetics & nucleic acid processing > transgenic animal |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Gene Regulation and Cell Proliferation CSHL Cancer Center Shared Resources > Animal Services CSHL Cancer Center Shared Resources > Animal Tissue and Imaging Service CSHL Cancer Center Shared Resources > Antibody and Phage Display Service CSHL Cancer Center Shared Resources > Microscopy Service CSHL labs > Krainer lab |
| Depositing User: | Matt Covey |
| Date: | 12 January 2015 |
| Date Deposited: | 30 Jan 2015 20:42 |
| Last Modified: | 15 Jul 2021 19:22 |
| PMCID: | PMC4318145 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/31167 |
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