Increased neuronal glutathione and neuroprotection in GTRAP3-18-deficient mice

Koji Aoyama; Fan Wang; Nobuko Matsumura; Hiroshi Kiyonari; Go Shioi; Karo Tanaka; Chisato Kinoshita; Kazue Kikuchi-Utsumi; Masahiko Watabe; Toshio Nakaki

doi:10.1016/j.nbd.2011.12.016

Increased neuronal glutathione and neuroprotection in GTRAP3-18-deficient mice

Neurobiol Dis. 2012 Mar;45(3):973-82. doi: 10.1016/j.nbd.2011.12.016. Epub 2011 Dec 14.

Authors

Koji Aoyama¹, Fan Wang, Nobuko Matsumura, Hiroshi Kiyonari, Go Shioi, Karo Tanaka, Chisato Kinoshita, Kazue Kikuchi-Utsumi, Masahiko Watabe, Toshio Nakaki

Affiliation

¹ Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.

PMID: 22210510
DOI: 10.1016/j.nbd.2011.12.016

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analysis of Variance
Animals
Brain / cytology*
Calcium-Binding Proteins / metabolism
Carrier Proteins / genetics*
Cysteine / metabolism
Excitatory Amino Acid Transporter 3 / metabolism
Exploratory Behavior / drug effects
Exploratory Behavior / physiology
Glial Fibrillary Acidic Protein / metabolism
Glutamic Acid / metabolism
Glutathione / metabolism*
Glycine / metabolism
Heat-Shock Proteins
Hippocampus / cytology
Hippocampus / drug effects
Hippocampus / metabolism
In Vitro Techniques
Maze Learning / drug effects
Maze Learning / physiology
Membrane Transport Proteins
Mice
Mice, Inbred C57BL
Mice, Knockout
Microfilament Proteins / metabolism
Molsidomine / analogs & derivatives
Molsidomine / pharmacology
Motor Activity / drug effects
Motor Activity / genetics
Neurons / drug effects
Neurons / metabolism*
Nitric Oxide Donors / pharmacology
Phenotype
Phosphopyruvate Hydratase / metabolism
Time Factors
gamma-Aminobutyric Acid / metabolism

Substances

Aif1 protein, mouse
Arl6ip5 protein, mouse
Calcium-Binding Proteins
Carrier Proteins
Excitatory Amino Acid Transporter 3
Glial Fibrillary Acidic Protein
Heat-Shock Proteins
Membrane Transport Proteins
Microfilament Proteins
Nitric Oxide Donors
Slc1a1 protein, mouse
Glutamic Acid
gamma-Aminobutyric Acid
linsidomine
Molsidomine
Phosphopyruvate Hydratase
Glutathione
Cysteine
Glycine