期刊
JOURNAL OF NEUROSCIENCE
卷 36, 期 13, 页码 3811-3820出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2396-15.2016
关键词
GAP43; local translation; motor neuron; RNA trafficking; SMA; SMN
资金
- Families of SMA/Cure SMA
- Muscular Dystrophy Association
- Weisman Family Foundation
- National Institutes of Health [NS091749]
- National Research Service [F31NS084730-01]
- Achievement Rewards for College Scientists Foundation (Roche Foundation Award)
Spinal muscular atrophy (SMA) is a neurodegenerative disease primarily affecting spinal motor neurons. It is caused by reduced levels of the survival of motor neuron (SMN) protein, which plays an essential role in the biogenesis of spliceosomal small nuclear ribonucleoproteins in all tissues. The etiology of the specific defects in the motor circuitry in SMA is still unclear, but SMN has also been implicated in mediating the axonal localization of mRNA-protein complexes, which may contribute to the axonal degeneration observed in SMA. Here, we report that SMN deficiency severely disrupts local protein synthesis within neuronal growth cones. We also identify the cytoskeleton-associated growth-associated protein 43 (GAP43) mRNA as a new target of SMN and show that motor neurons from SMA mouse models have reduced levels of GAP43 mRNA and protein in axons and growth cones. Importantly, overexpression of two mRNA-binding proteins, HuD and IMP1, restores GAP43 mRNA and protein levels in growth cones and rescues axon outgrowth defects in SMA neurons. These findings demonstrate that SMN plays an important role in the localization and local translation of mRNAs with important axonal functions and suggest that disruption of this function may contribute to the axonal defects observed in SMA.
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