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

• Type of Material: Article
• Authors: Claudia Fallini, Emory University; Paul G. Donlin-Asp, Emory University; Jeremy P. Rouanet, Emory University; Gary Bassell, Emory University; Wilfried Rossoll, Emory University
• Language: English
• Date: 2016-03-30
• Publisher: Society for Neuroscience
• Publication Version: Final Published Version
• Copyright Statement: © 2016 the authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.2396-15.2016
• Title of Journal or Parent Work: Journal of Neuroscience
• ISSN: 0270-6474
• Volume: 36
• Issue: 13
• Start Page: 3811
• End Page: 3820
• Grant/Funding Information: 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: SMALL NUCLEAR RIBONUCLEOPROTEIN; AXON OUTGROWTH; SMA; GAP43; Neurosciences & Neurology; SMN PROTEIN; Life Sciences & Biomedicine; NEUROMUSCULAR-JUNCTION; SPINAL MUSCULAR-ATROPHY; NERVOUS-SYSTEM; SMN; local translation; MOUSE MODEL; Neurosciences; motor neuron; RNA trafficking
• Research Categories: Biology, Neuroscience; Health Sciences, General; Biology, Cell

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.