Increased neuronal glutathione and neuroprotection in GTRAP3-18-deficient mice.
Glutathione (GSH) is an important neuroprotective molecule in the brain. The strategy to increase neuronal GSH level is a promising approach to the treatment of neurodegenerative diseases. However, the regulatory mechanism by which neuron-specific GSH synthesis is facilitated remains elusive. Glutamate transporter-associated protein 3-18 (GTRAP3-18) is an endoplasmic reticulum protein interacting with excitatory amino acid carrier 1 (EAAC1), which is a neuronal glutamate/cysteine transporter. To investigate the potential regulatory mechanism to increase neuronal GSH level in vivo, we generated GTRAP3-18-deficient (GTRAP3-18(-/-)) mice using a gene-targeting approach. Disruption of the GTRAP3-18 gene resulted in increased EAAC1 expression in the plasma membrane, increased neuronal GSH content and neuroprotection against oxidative stress. In addition, GTRAP3-18(-/-) mice performed better in motor/spatial learning and memory tests than wild-type mice. Therefore, the suppression of GTRAP3-18 increases neuronal resistance to oxidative stress by increasing GSH content and also facilitates cognitive function. The present results may provide a molecular basis for the development of treatments for neurodegenerative diseases.
Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Koji
K
Aoyama
Fan
F
Wang
Nobuko
N
Matsumura
Hiroshi
H
Kiyonari
Go
G
Shioi
Karo
K
Tanaka
Chisato
C
Kinoshita
Kazue
K
Kikuchi-Utsumi
Masahiko
M
Watabe
Toshio
T
Nakaki
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000166:cytology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D003545:Cysteine / Q000378:metabolism; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D005998:Glycine / Q000378:metabolism; D006360:Heat-Shock Proteins; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010641:Phenotype; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C491049:Aif1 protein, mouse; C464502:Arl6ip5 protein, mouse; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D050580:Excitatory Amino Acid Transporter 3; D005904:Glial Fibrillary Acidic Protein; D006360:Heat-Shock Proteins; D026901:Membrane Transport Proteins; D008840:Microfilament Proteins; D020030:Nitric Oxide Donors; C493399:Slc1a1 protein, mouse; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C002385:linsidomine; D008981:Molsidomine; D010751:Phosphopyruvate Hydratase; D005978:Glutathione; D003545:Cysteine; D005998:Glycine