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

Authors

  • Irene Llorente-Folch,

    1. Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa UAM-CSIC, and CIBER de Enfermedades Raras (CIBERER), Universidad Autónoma de Madrid, Madrid, Spain
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  • Ignasi Sahún,

    1. Programme of Genes and Disease, Center for Genomic Regulation, and CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
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  • Laura Contreras,

    1. Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa UAM-CSIC, and CIBER de Enfermedades Raras (CIBERER), Universidad Autónoma de Madrid, Madrid, Spain
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  • María José Casarejos,

    1. Department of Neurobiology and CIBERNED, Hospital Ramón y Cajal, Carretera de Colmenar km 9,1, Madrid, Spain
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  • Josep María Grau,

    1. Department of Internal Medicine and Pathology, Hospital Clinic, University of Barcelona Medical School, Barcelona, Spain
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  • Takeyori Saheki,

    1. Institute of Resource Development and Analysis, Kumamoto University 2-2-1 Honjo, Kumamoto, Japan
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  • María Angeles Mena,

    1. Department of Neurobiology and CIBERNED, Hospital Ramón y Cajal, Carretera de Colmenar km 9,1, Madrid, Spain
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  • Jorgina Satrústegui,

    1. Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa UAM-CSIC, and CIBER de Enfermedades Raras (CIBERER), Universidad Autónoma de Madrid, Madrid, Spain
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  • Mara Dierssen,

    1. Programme of Genes and Disease, Center for Genomic Regulation, and CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain
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  • Beatriz Pardo

    Corresponding author
    • Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa UAM-CSIC, and CIBER de Enfermedades Raras (CIBERER), Universidad Autónoma de Madrid, Madrid, Spain
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Address correspondence and reprint requests to Beatriz Pardo, Centro de Biología Molecular Severo Ochoa UAM-CSIC, and CIBER de Enfermedades Raras (CIBERER), Universidad Autónoma de Madrid, 28049-Madrid, Spain. E-mail: bpardo@cbm.uam.es

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.

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