Deficiency of the survival of motor neuron protein impairs mrna localization and local translation in the growth cone of motor neurons

Claudia Fallini, Paul G. Donlin-Asp, Jeremy P. Rouanet, Gary J. Bassell, Wilfried Rossoll

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3811-3820
Number of pages10
JournalJournal of Neuroscience
Volume36
Issue number13
DOIs
StatePublished - Mar 30 2016

Keywords

  • GAP43
  • Local translation
  • Motor neuron
  • RNA trafficking
  • SMA
  • SMN

ASJC Scopus subject areas

  • Neuroscience(all)

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