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Glutathione Articles - Neurodegenerative Diseases
Regulation of Neuronal Glutathione Synthesis
Aoyama K, Watabe M, Nakaki T
J Pharmacol Sci 108, 227 – 238 (2008)
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ABSTRACT
The brain is among the major
organs generating large amounts of reactive oxygen species and is especially
susceptible to oxidative stress. Glutathione (GSH) plays critical roles as
an antioxidant, enzyme cofactor, cysteine storage form, the major redox
buffer, and a neuromodulator
in the central nervous system. GSH deficiency has been implicated in
neurodegenerative diseases. GSH is a tripeptide comprised of glutamate,
cysteine, and glycine. Cysteine is the rate-limiting substrate for GSH
synthesis within neurons. Most neuronal cysteine
uptake is mediated by sodium-dependent excitatory amino acid transporter
(EAAT) systems, known as excitatory amino acid carrier 1 (EAAC1). Previous
studies demonstrated EAAT is vulnerable to oxidative stress, leading to
impaired function. A recent study found EAAC1-
deficient mice to have decreased brain GSH levels and increased
susceptibility to oxidative stress. The function of EAAC1 is also regulated
by glutamate transporter associated protein 3-18. This review focuses on the
mechanisms underlying GSH synthesis, especially those related
to neuronal cysteine transport via EAAC1, as well as on the importance of
GSH functions against oxidative stress.
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