Journal of Molecular Neuroscience

, Volume 32, Issue 2, pp 120–131

Smn Depletion Alters Profilin II Expression and Leads to Upregulation of the RhoA/ROCK Pathway and Defects in Neuronal Integrity

Article

Abstract

Spinal muscular atrophy (SMA) is the most common genetic disease resulting in infant mortality due to severe loss of α-motor neurons. SMA is caused by mutations or deletions of the ubiquitously expressed survival motor neuron (SMN) gene. However, why α-motor neurons of SMA patients are specifically affected is not clear. We demonstrate here that Smn knockdown in PC12 cells alters the expression pattern of profilin II, resulting in an increase in the neuronal-specific profilin IIa isoform. Moreover, the depletion of Smn, a known interacting partner of profilin IIa, further contributes to the increased profilin IIa availability. Altogether, this leads to an increased formation of ROCK/profilin IIa complex and an inappropriate activation of the RhoA/ROCK pathway, resulting in altered cytoskeletal integrity and a subsequent defect in neuritogenesis. This study represents the first description of a mechanism underlying SMA pathogenesis and highlights new targets for therapeutic intervention for this devastating disorder.

Keywords

Spinal muscular atrophy Survival motor neuron Smn knockdown Profilin IIa 

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Supplementary material

12031_2007_24_Fig7_ESM.gif (407 kb)
Supplementary Figure 1

Rat Smn cDNA (accession: AF044910) sequence and sh_Smn_519 targeted sequence (underlined and bold) used to knockdown Smn in PC12 cells (GIF 416 kb)

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Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Mélissa Bowerman
    • 1
    • 2
    • 3
  • Dina Shafey
    • 1
    • 2
    • 3
  • Rashmi Kothary
    • 1
    • 2
    • 3
    • 4
  1. 1.Ottawa Health Research InstituteOttawaCanada
  2. 2.The University of Ottawa Center for Neuromuscular DiseaseOttawaCanada
  3. 3.Department of Cellular and Molecular MedicineUniversity of OttawaOttawaCanada
  4. 4.Department of MedicineUniversity of OttawaOttawaCanada

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