Decay in survival motor neuron and plastin 3 levels during differentiation of iPSC-derived human motor neurons

Sci Rep. 2015 Jun 26;5:11696. doi: 10.1038/srep11696.

Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in Survival Motor Neuron 1 (SMN1), leading to degeneration of alpha motor neurons (MNs) but also affecting other cell types. Induced pluripotent stem cell (iPSC)-derived human MN models from severe SMA patients have shown relevant phenotypes. We have produced and fully characterized iPSCs from members of a discordant consanguineous family with chronic SMA. We differentiated the iPSC clones into ISL-1+/ChAT+ MNs and performed a comparative study during the differentiation process, observing significant differences in neurite length and number between family members. Analyses of samples from wild-type, severe SMA type I and the type IIIa/IV family showed a progressive decay in SMN protein levels during iPSC-MN differentiation, recapitulating previous observations in developmental studies. PLS3 underwent parallel reductions at both the transcriptional and translational levels. The underlying, progressive developmental decay in SMN and PLS3 levels may lead to the increased vulnerability of MNs in SMA disease. Measurements of SMN and PLS3 transcript and protein levels in iPSC-derived MNs show limited value as SMA biomarkers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cell Differentiation*
  • Cell Survival
  • Clone Cells
  • Coculture Techniques
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Male
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Microfilament Proteins / metabolism*
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology*
  • Muscle Fibers, Skeletal / cytology
  • Neurites / metabolism
  • Pedigree
  • Survival of Motor Neuron 1 Protein / metabolism*

Substances

  • Biomarkers
  • Membrane Glycoproteins
  • Microfilament Proteins
  • SMN1 protein, human
  • Survival of Motor Neuron 1 Protein
  • plastin