Preferential vulnerability of mesencephalic dopamine neurons to glutamate transporter dysfunction.
Nigral depletion of the main brain antioxidant GSH is the earliest biochemical event involved in Parkinson's disease pathogenesis. Its causes are completely unknown but increasing number of evidence suggests that glutamate transporters [excitatory amino acid transporters (EAATs)] are the main route by which GSH precursors may enter the cell. In this study, we report that dopamine (DA) neurons, which express the excitatory amino acid carrier 1, are preferentially affected by EAAT dysfunction when compared with non-DA neurons. In rat embryonic mesencephalic cultures, l-trans-pyrrolidine-2,4-dicarboxylate, a substrate inhibitor of EAATs, is directly and preferentially toxic for DA neurons by decreasing the availability of GSH precursors and lowering their resistance threshold to glutamate excitotoxicity through NMDA-receptors. In adult rat, acute intranigral injection of l-trans-pyrrolidine-2,4-dicarboxylate induces a large regionally selective and dose-dependent loss of DA neurons and alpha-synuclein aggregate formation. These data highlight for the first time the importance of excitatory amino acid carrier 1 function for the maintenance of antioxidant defense in DA neurons and suggest its dysfunction as a candidate mechanism for the selective death of DA neurons such as occurring in Parkinson's disease.
Equipe Interactions Cellulaires, Neurodégénérescence et Neuroplasticité, Institut de Biologie du Développement de Marseille-Luminy, UMR6216 CNRS-Université de la Méditerranée, Marseille, France.
Imane
I
Nafia
Diane B
DB
Re
Frédérique
F
Masmejean
Christophe
C
Melon
Philippe
P
Kachidian
Lydia
L
Kerkerian-Le Goff
André
A
Nieoullon
Laurence
L
Had-Aissouni
D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D002478:Cells, Cultured; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D027341:Excitatory Amino Acid Transporter 1 / Q000502:physiology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity; D008636:Mesencephalon / Q000166:cytology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011247:Pregnancy; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
D003998:Dicarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D027341:Excitatory Amino Acid Transporter 1; D005904:Glial Fibrillary Acidic Protein; D014179:Neurotransmitter Uptake Inhibitors; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; C083486:pyrrolidine-2,4-dicarboxylic acid; D014446:Tyrosine 3-Monooxygenase; D010751:Phosphopyruvate Hydratase; D004298:Dopamine