Spinal muscular atrophy pathogenic mutations impair the axonogenic properties of axonal-survival of motor neuron

Denise Locatelli, Paolo D'Errico, Silvia Capra, Adele Finardi, Francesca Colciaghi, Veronica Setola, Mineko Terao, Enrico Garattini, Giorgio Battaglia

Research output: Contribution to journalArticlepeer-review

Abstract

The axonal survival of motor neuron (a-SMN) protein is a truncated isoform of SMN1, the spinal muscular atrophy (SMA) disease gene. a-SMN is selectively localized in axons and endowed with remarkable axonogenic properties. At present, the role of a-SMN in SMA is unknown. As a first step to verify a link between a-SMN and SMA, we investigated by means of over-expression experiments in neuroblastoma-spinal cord hybrid cell line (NSC34) whether SMA pathogenic mutations located in the N-terminal part of the protein affected a-SMN function. We demonstrated here that either SMN1 missense mutations or small intragenic re-arrangements located in the Tudor domain consistently altered the a-SMN capability of inducing axonal elongation in vitro. Mutated human a-SMN proteins determined in almost all NSC34 motor neurons the growth of short axons with prominent morphologic abnormalities. Our data indicate that the Tudor domain is critical in dictating a-SMN function possibly because it is an association domain for proteins involved in axon growth. They also indicate that Tudor domain mutations are functionally relevant not only for FL-SMN but also for a-SMN, raising the possibility that also a-SMN loss of function may contribute to the pathogenic steps leading to SMA.

Original languageEnglish
Pages (from-to)465-474
Number of pages10
JournalJournal of Neurochemistry
Volume121
Issue number3
DOIs
Publication statusPublished - May 2012

Keywords

  • axon growth
  • axon swellings
  • cytoskeletal abnormalities
  • motor neuron
  • spinal muscular atrophy
  • Tudor domain

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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