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Título: | AGC1-malate aspartate shuttle activity is critical for dopamine handling in the nigrostriatal pathway |
Autor: | Llorente-Folch, Irene CSIC; Sahún, Ignasi; Contreras, Laura CSIC; Casarejos, María José; Grau-Junyent, Josep María; Saheki, T.; Mena, María Ángeles; Satrústegui, Jorgina CSIC ORCID; Dierssen, Mara CSIC; Pardo, Beatriz CSIC ORCID | Palabras clave: | Global cerebral hypomyelination Dopamine AGC-1 deficiency Malate-aspartate shuttle OmniBank®, VMAT2 |
Fecha de publicación: | 2013 | Editor: | Blackwell Publishing | Citación: | Journal of Neurochemistry 124: 347- 362 (2013) | Resumen: | 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. | URI: | http://hdl.handle.net/10261/95338 | DOI: | 10.1111/jnc.12096 | Identificadores: | doi: 10.1111/jnc.12096 issn: 0022-3042 |
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