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

Journal of neurochemistry (2012-12-12)
Irene Llorente-Folch, Ignasi Sahún, Laura Contreras, María José Casarejos, Josep María Grau, Takeyori Saheki, María Angeles Mena, Jorgina Satrústegui, Mara Dierssen, Beatriz Pardo
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
DL-Malic acid, ReagentPlus®, ≥99%
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DL-Malic acid, ≥98% (capillary GC)
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DL-Malic acid, 99%
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D-(+)-Malic acid, unnatural form, ≥97.0% (T)
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Malic acid, meets USP/NF testing specifications
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DL-Malic acid disodium salt, ≥95% (capillary GC)
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L-(−)-Malic acid disodium salt, 95-100% (enzymatic)
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DL-Malic acid, meets analytical specification of FCC, E296, 99-100.5% (alkalimetric)
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Anti-Vesicular Monoamine Transporter 2 Antibody, Chemicon®, from rabbit
Supelco
D-Malic acid, analytical standard

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