Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse.
Uptake of the neurotransmitter glutamate is effected primarily by transporters expressed on astrocytes, and downregulation of these transporters leads to seizures and neuronal death. Neurons also express a glutamate transporter, termed excitatory amino acid carrier-1 (EAAC1), but the physiological function of this transporter remains uncertain. Here we report that genetically EAAC1-null (Slc1a1(-/-)) mice have reduced neuronal glutathione levels and, with aging, develop brain atrophy and behavioral changes. EAAC1 can also rapidly transport cysteine, an obligate precursor for neuronal glutathione synthesis. Neurons in the hippocampal slices of EAAC1(-/-) mice were found to have reduced glutathione content, increased oxidant levels and increased susceptibility to oxidant injury. These changes were reversed by treating the EAAC1(-/-) mice with N-acetylcysteine, a membrane-permeable cysteine precursor. These findings suggest that EAAC1 is the primary route for neuronal cysteine uptake and that EAAC1 deficiency thereby leads to impaired neuronal glutathione metabolism, oxidative stress and age-dependent neurodegeneration.
Aoyama
Koji
K
Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA.
Suh
Sang Won
SW
Hamby
Aaron M
AM
Liu
Jialing
J
Chan
Wai Yee
WY
Chen
Yongmei
Y
Swanson
Raymond A
RA
D000111:Acetylcysteine / Q000494:pharmacology; D000375:Aging / Q000473:pathology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001640:Bicuculline / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D003545:Cysteine / Q000378:metabolism; D050580:Excitatory Amino Acid Transporter 3 / Q000235:genetics*; D018756:GABA Antagonists / Q000494:pharmacology; D005838:Genotype; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism*; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000502:physiology
D050580:Excitatory Amino Acid Transporter 3; D018756:GABA Antagonists; D016877:Oxidants; C493399:Slc1a1 protein, mouse; D005978:Glutathione; D003545:Cysteine; D000111:Acetylcysteine; D001640:Bicuculline