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.
© 2012 International Society for Neurochemistry.
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