Deficiency of Mitochondrial Aspartate-Glutamate Carrier 1 Leads to Oligodendrocyte Precursor Cell Proliferation Defects Both In Vitro and In Vivo

Int J Mol Sci. 2019 Sep 11;20(18):4486. doi: 10.3390/ijms20184486.

Abstract

Aspartate-Glutamate Carrier 1 (AGC1) deficiency is a rare neurological disease caused by mutations in the solute carrier family 25, member 12 (SLC25A12) gene, encoding for the mitochondrial aspartate-glutamate carrier isoform 1 (AGC1), a component of the malate-aspartate NADH shuttle (MAS), expressed in excitable tissues only. AGC1 deficiency patients are children showing severe hypotonia, arrested psychomotor development, seizures and global hypomyelination. While the effect of AGC1 deficiency in neurons and neuronal function has been deeply studied, little is known about oligodendrocytes and their precursors, the brain cells involved in myelination. Here we studied the effect of AGC1 down-regulation on oligodendrocyte precursor cells (OPCs), using both in vitro and in vivo mouse disease models. In the cell model, we showed that a reduced expression of AGC1 induces a deficit of OPC proliferation leading to their spontaneous and precocious differentiation into oligodendrocytes. Interestingly, this effect seems to be related to a dysregulation in the expression of trophic factors and receptors involved in OPC proliferation/differentiation, such as Platelet-Derived Growth Factor α (PDGFα) and Transforming Growth Factor βs (TGFβs). We also confirmed the OPC reduction in vivo in AGC1-deficent mice, as well as a proliferation deficit in neurospheres from the Subventricular Zone (SVZ) of these animals, thus indicating that AGC1 reduction could affect the proliferation of different brain precursor cells. These data clearly show that AGC1 impairment alters myelination not only by acting on N-acetyl-aspartate production in neurons but also on OPC proliferation and suggest new potential therapeutic targets for the treatment of AGC1 deficiency.

Keywords: AGC1 deficiency; growth factors; mitochondrial disease; mouse model; subventricular zone.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amino Acid Transport Systems, Acidic / deficiency*
  • Amino Acid Transport Systems, Acidic / metabolism
  • Animals
  • Antiporters / deficiency*
  • Antiporters / metabolism
  • Cell Differentiation
  • Cell Line
  • Cell Proliferation
  • Down-Regulation
  • Gene Silencing
  • Lactates / metabolism
  • Lateral Ventricles / metabolism
  • Membrane Potential, Mitochondrial
  • Mice
  • Mitochondria / metabolism*
  • Neurons / metabolism
  • Oligodendrocyte Precursor Cells / cytology*
  • Oligodendrocyte Precursor Cells / metabolism*
  • Platelet-Derived Growth Factor
  • Reactive Oxygen Species / metabolism
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / drug effects
  • Transforming Growth Factor beta / metabolism

Substances

  • Amino Acid Transport Systems, Acidic
  • Antiporters
  • Lactates
  • Platelet-Derived Growth Factor
  • Reactive Oxygen Species
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • aspartate-glutamate carrier
  • platelet-derived growth factor A
  • Adenosine Triphosphate