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Author Notes:

Correspondence should be addressed to either Wilfried Rossoll, PhD, or Gary J. Bassell, PhD, Emory University School of Medicine, Whitehead Biomedical Research Building, Room 415, 615 Michael St NE, Atlanta, GA, E-mail: wrossol@emory.edu or bassel@emory.edu.

C.F., G.J.B., and W.R. designed research.

C.F., P.G.D.-A., and J.P.R. performed research.

C.F., P.G.D.-A., J.P.R., G.J.B., and W.R. analyzed data.

C.F. and W.R. wrote the paper.

C.F. and P.G.D.-A., contributed equally to this work.

We thank Lian Li and Latoya Rowe for excellent technical support.

The authors declare no competing financial interests.

Subjects:

Research Funding:

This work was supported by Families of SMA/Cure SMA (W.R. and C.F.); the Muscular Dystrophy Association and the Weisman Family Foundation (G.J.B.); the National Institutes of Health (Grant NS091749 to W.R.); the National Research Service (Training Grant F31NS084730-01), and the Achievement Rewards for College Scientists Foundation (Roche Foundation Award to P.G.D.-A.).

Keywords:

  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • GAP43
  • local translation
  • motor neuron
  • RNA trafficking
  • SMA
  • SMN
  • SPINAL MUSCULAR-ATROPHY
  • SMALL NUCLEAR RIBONUCLEOPROTEIN
  • SMN PROTEIN
  • NERVOUS-SYSTEM
  • AXON OUTGROWTH
  • MOUSE MODEL
  • NEUROMUSCULAR-JUNCTION

Deficiency of the Survival of Motor Neuron Protein Impairs mRNA Localization and Local Translation in the Growth Cone of Motor Neurons

Tools:

Journal Title:

Journal of Neuroscience

Volume:

Volume 36, Number 13

Publisher:

, Pages 3811-3820

Type of Work:

Article | Final Publisher PDF

Abstract:

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 mRNAbinding proteins, HuD and IMP1, restores GAP43 mRNA and protein levels in growth cones and rescues axon outgrowth defects in SMA neurons. These findings demonstrate thatSMNplays an important role in the localization and local translation ofmRNAswith important axonal functions and suggest that disruption of this function may contribute to the axonal defects observed in SMA.

Copyright information:

© 2016 the authors

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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