title: AGC1-malate aspartate shuttle activity is critical for dopamine handling in the nigrostriatal pathway.
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.
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa UAM-CSIC, and CIBER de Enfermedades Raras (CIBERER), Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Llorente-Folch
authors.forename: Ignasi
authors.initials: I
authors.lastname: Sahún
authors.forename: Laura
authors.initials: L
authors.lastname: Contreras
authors.forename: María José
authors.initials: MJ
authors.lastname: Casarejos
authors.forename: Josep María
authors.initials: JM
authors.lastname: Grau
authors.forename: Takeyori
authors.initials: T
authors.lastname: Saheki
authors.forename: María Angeles
authors.initials: MA
authors.lastname: Mena
authors.forename: Jorgina
authors.initials: J
authors.lastname: Satrústegui
authors.forename: Mara
authors.initials: M
authors.lastname: Dierssen
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pardo
mesh_terms: D026922:Amino Acid Transport Systems, Acidic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017920:Antiporters / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D001224:Aspartic Acid / Q000378:metabolism* / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D004298:Dopamine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004644:Emotions / Q000502:physiology; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008293:Malates / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D033681:Mitochondrial Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019957:Motor Skills Disorders / Q000235:genetics / Q000378:metabolism; D009434:Neural Pathways / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology; D011247:Pregnancy; D011596:Psychomotor Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism*
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D017920:Antiporters; D008293:Malates; D033681:Mitochondrial Membrane Transport Proteins; C491956:Slc25a12 protein, mouse; D001224:Aspartic Acid; C030298:malic acid; D004298:Dopamine