AGC1-malate aspartate shuttle activity is critical for dopamine handling in the nigrostriatal pathway

J Neurochem. 2013 Feb;124(3):347-62. doi: 10.1111/jnc.12096.

Abstract

The mitochondrial transporter of aspartate-glutamate Aralar/AGC1 is a regulatory component of the malate-aspartate shuttle. Aralar deficiency in mouse and human causes a shutdown of brain shuttle activity and global cerebral hypomyelination. A lack of neurofilament-labeled processes is detected in the cerebral cortex, but whether different types of neurons are differentially affected by Aralar deficiency is still unknown. We have now found that Aralar-knockout (Aralar-KO) post-natal mice show hyperactivity, anxiety-like behavior, and hyperreactivity with a decrease of dopamine (DA) in terminal-rich regions. The striatum is the brain region most affected in terms of size, amino acid and monoamine content. We find a decline in vesicular monoamine transporter-2 (VMAT2) levels associated with increased DA metabolism through MAO activity (DOPAC/DA ratio) in Aralar-KO striatum. However, no decrease in DA or in the number of nigral tyrosine hydroxylase-positive cells was detected in Aralar-KO brainstem. Adult Aralar-hemizygous mice presented also increased DOPAC/DA ratio in striatum and enhanced sensitivity to amphetamine. Our results suggest that Aralar deficiency causes a fall in GSH/GSSG ratio and VMAT2 in striatum that might be related to a failure to produce mitochondrial NADH and to an increase of reactive oxygen species (ROS) in the cytosol. The results indicate that the nigrostriatal dopaminergic system is a target of Aralar deficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport Systems, Acidic / deficiency
  • Amino Acid Transport Systems, Acidic / genetics
  • Amino Acid Transport Systems, Acidic / metabolism
  • Animals
  • Antiporters / deficiency
  • Antiporters / genetics
  • Antiporters / metabolism
  • Aspartic Acid / metabolism*
  • Aspartic Acid / physiology
  • Corpus Striatum / cytology
  • Corpus Striatum / metabolism*
  • Dopamine / deficiency
  • Dopamine / genetics
  • Dopamine / metabolism*
  • Emotions / physiology
  • Exploratory Behavior / physiology
  • Female
  • Hereditary Central Nervous System Demyelinating Diseases / genetics
  • Hereditary Central Nervous System Demyelinating Diseases / metabolism*
  • Hereditary Central Nervous System Demyelinating Diseases / physiopathology
  • Malates / metabolism*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / metabolism*
  • Mitochondrial Diseases / physiopathology
  • Mitochondrial Membrane Transport Proteins / deficiency
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Motor Skills Disorders / genetics
  • Motor Skills Disorders / metabolism
  • Neural Pathways / cytology
  • Neural Pathways / metabolism
  • Neural Pathways / physiopathology
  • Oxidative Stress / physiology
  • Pregnancy
  • Psychomotor Disorders / genetics
  • Psychomotor Disorders / metabolism*
  • Psychomotor Disorders / physiopathology
  • Substantia Nigra / cytology
  • Substantia Nigra / metabolism*

Substances

  • Amino Acid Transport Systems, Acidic
  • Antiporters
  • Malates
  • Mitochondrial Membrane Transport Proteins
  • Slc25a12 protein, mouse
  • Aspartic Acid
  • malic acid
  • Dopamine

Supplementary concepts

  • Hypomyelination, Global Cerebral