α-COP binding to the survival motor neuron protein SMN is required for neuronal process outgrowth

Hum Mol Genet. 2015 Dec 20;24(25):7295-307. doi: 10.1093/hmg/ddv428. Epub 2015 Oct 13.

Abstract

Spinal muscular atrophy (SMA), a heritable neurodegenerative disease, results from insufficient levels of the survival motor neuron (SMN) protein. α-COP binds to SMN, linking the COPI vesicular transport pathway to SMA. Reduced levels of α-COP restricted development of neuronal processes in NSC-34 cells and primary cortical neurons. Remarkably, heterologous expression of human α-COP restored normal neurite length and morphology in SMN-depleted NSC-34 cells in vitro and zebrafish motor neurons in vivo. We identified single amino acid mutants of α-COP that selectively abrogate SMN binding, retain COPI-mediated Golgi-ER trafficking functionality, but were unable to support neurite outgrowth in cellular and zebrafish models of SMA. Taken together, these demonstrate the functional role of COPI association with the SMN protein in neuronal development.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Cells, Cultured
  • Coatomer Protein / genetics
  • Coatomer Protein / metabolism*
  • Fluorescent Antibody Technique
  • Humans
  • Immunoprecipitation
  • Motor Neurons / metabolism*
  • Muscular Atrophy, Spinal / metabolism*
  • Neurites / metabolism
  • Protein Binding
  • Survival of Motor Neuron 1 Protein / genetics
  • Survival of Motor Neuron 1 Protein / metabolism*
  • Zebrafish

Substances

  • Coatomer Protein
  • Survival of Motor Neuron 1 Protein