PMID- 16311588
OWN - NLM
STAT- MEDLINE
DCOM- 20060227
LR  - 20131121
IS  - 1097-6256 (Print)
IS  - 1097-6256 (Linking)
VI  - 9
IP  - 1
DP  - 2006 Jan
TI  - Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 
      deficient mouse.
PG  - 119-26
AB  - 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.
FAU - Aoyama, Koji
AU  - Aoyama K
AD  - Department of Neurology, University of California San Francisco, San Francisco, 
      California 94143, USA.
FAU - Suh, Sang Won
AU  - Suh SW
FAU - Hamby, Aaron M
AU  - Hamby AM
FAU - Liu, Jialing
AU  - Liu J
FAU - Chan, Wai Yee
AU  - Chan WY
FAU - Chen, Yongmei
AU  - Chen Y
FAU - Swanson, Raymond A
AU  - Swanson RA
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20051127
PL  - United States
TA  - Nat Neurosci
JT  - Nature neuroscience
JID - 9809671
RN  - 0 (Excitatory Amino Acid Transporter 3)
RN  - 0 (GABA Antagonists)
RN  - 0 (Oxidants)
RN  - 0 (Slc1a1 protein, mouse)
RN  - GAN16C9B8O (Glutathione)
RN  - K848JZ4886 (Cysteine)
RN  - WYQ7N0BPYC (Acetylcysteine)
RN  - Y37615DVKC (Bicuculline)
SB  - IM
MH  - Acetylcysteine/pharmacology
MH  - Aging/*pathology
MH  - Animals
MH  - Behavior, Animal/drug effects
MH  - Bicuculline/pharmacology
MH  - Blotting, Western
MH  - Brain/pathology
MH  - Cysteine/metabolism
MH  - Excitatory Amino Acid Transporter 3/*genetics
MH  - GABA Antagonists/pharmacology
MH  - Genotype
MH  - Glutathione/*deficiency/metabolism
MH  - Immunohistochemistry
MH  - Mice
MH  - Mice, Knockout
MH  - Nerve Degeneration/*genetics/*pathology
MH  - Neurons/*metabolism
MH  - Oxidants/toxicity
MH  - Oxidative Stress/physiology
EDAT- 2005/11/29 09:00
MHDA- 2006/02/28 09:00
CRDT- 2005/11/29 09:00
PHST- 2005/09/13 00:00 [received]
PHST- 2005/10/28 00:00 [accepted]
PHST- 2005/11/29 09:00 [pubmed]
PHST- 2006/02/28 09:00 [medline]
PHST- 2005/11/29 09:00 [entrez]
AID - nn1609 [pii]
AID - 10.1038/nn1609 [doi]
PST - ppublish
SO  - Nat Neurosci. 2006 Jan;9(1):119-26. doi: 10.1038/nn1609. Epub 2005 Nov 27.