Spinal muscular atrophy astrocytes exhibit abnormal calcium regulation and reduced growth factor production

Glia. 2013 Sep;61(9):1418-1428. doi: 10.1002/glia.22522. Epub 2013 Jul 10.

Abstract

Spinal muscular atrophy (SMA) is a genetic disorder caused by the deletion of the survival motor neuron 1 (SMN1) gene that leads to loss of motor neurons in the spinal cord. Although motor neurons are selectively lost during SMA pathology, selective replacement of SMN in motor neurons does not lead to full rescue in mouse models. Due to the ubiquitous expression of SMN, it is likely that other cell types besides motor neurons are affected by its disruption and therefore may contribute to disease pathology. Here we show that astrocytes in SMAΔ7 mouse spinal cord and from SMA-induced pluripotent stem cells exhibit morphological and cellular changes indicative of activation before overt motor neuron loss. Furthermore, our in vitro studies show mis-regulation of basal calcium and decreased response to adenosine triphosphate stimulation indicating abnormal astrocyte function. Together, for the first time, these data show early disruptions in astrocytes that may contribute to SMA disease pathology.

Keywords: astrocyte activation; cell autonomous; motor neurons; stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / pharmacology
  • Age Factors
  • Aldehyde Dehydrogenase / metabolism
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Calcium / metabolism*
  • Cell Line, Transformed
  • Choline O-Acetyltransferase / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation, Developmental / genetics
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism*
  • Glial Fibrillary Acidic Protein / metabolism
  • Humans
  • Mice
  • Mice, Transgenic
  • Muscular Atrophy, Spinal / genetics
  • Muscular Atrophy, Spinal / pathology*
  • Mutation / genetics
  • Nestin / metabolism
  • Oxidoreductases Acting on CH-NH Group Donors
  • Pluripotent Stem Cells / metabolism
  • Receptors, Purinergic P2Y2 / metabolism
  • S100 Proteins / metabolism
  • Spinal Cord / cytology*
  • Survival of Motor Neuron 1 Protein / genetics
  • Survival of Motor Neuron 2 Protein / metabolism

Substances

  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Fibrillary Acidic Protein
  • Nestin
  • Receptors, Purinergic P2Y2
  • S100 Proteins
  • SMN2 protein, human
  • Smn1 protein, mouse
  • Survival of Motor Neuron 1 Protein
  • Survival of Motor Neuron 2 Protein
  • Adenosine Triphosphate
  • Aldehyde Dehydrogenase
  • Oxidoreductases Acting on CH-NH Group Donors
  • formyltetrahydrofolate dehydrogenase
  • Choline O-Acetyltransferase
  • Calcium