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Cited by 226Sulfur Compounds in BiologyGlutathione Transferases and PolymorphismsRedox biology and oxidative stress

Impaired Glutathione Synthesis in Neurodegeneration

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Aoyama, Koji, Nakaki, Toshio·2013·International Journal of Molecular Sciences
DOI 10.3390/ijms141021021PMC PMC3821656
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Abstract

Glutathione (GSH) was discovered in yeast cells in 1888. Studies of GSH in mammalian cells before the 1980s focused exclusively on its function for the detoxication of xenobiotics or for drug metabolism in the liver, in which GSH is present at its highest concentration in the body. Increasing evidence has demonstrated other important roles of GSH in the brain, not only for the detoxication of xenobiotics but also for antioxidant defense and the regulation of intracellular redox homeostasis. GSH also regulates cell signaling, protein function, gene expression, and cell differentiation/proliferation in the brain. Clinically, inborn errors in GSH-related enzymes are very rare, but disorders of GSH metabolism are common in major neurodegenerative diseases showing GSH depletion and increased levels of oxidative stress in the brain. GSH depletion would precipitate oxidative damage in the brain, leading to neurodegenerative diseases. This review focuses on the significance of GSH function, the synthesis of GSH and its metabolism, and clinical disorders of GSH metabolism. A potential approach to increase brain GSH levels against neurodegeneration is also discussed.

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  • The amino acids cysteine and glycine liberated by hydrolysis are efficiently taken up by sodium-dependent transporters into neurons and can be used as substrates for neuronal GSH synthesis.

    “The amino acids liberated by the hydrolysis, cysteine and glycine, are efficiently taken up by sodium‐dependent transporters into neurons (Aoyama and Nakaki 2013; Zafra and Giménez 2008) and can be used as substrates for neuronal GSH synthesis (Dringen, Pfeiffer, et al. 1999; Kranich et al. 1996).”

    From Glutathione Metabolism of the Brain—The Role of Astrocytes (2025) · cites this paper as Aoyama and Nakaki 2013

    The ‘Excitatory Amino Acid Transporters’ section says that approximately 90% of neuronal cysteine uptake uses sodium-dependent systems. The ‘Thiol Source for Glutathione Synthesis in the Brain’ section says that cysteine and glycine released by hydrolysis are transported into neurons for GSH synthesis. Our copy does not establish that glycine uptake is sodium-dependent, so it supports only part of the uptake claim attributed to this citation. (LLM, conf=0.88)

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Authors
Aoyama, K., & Nakaki, T.
Affiliations
Teikyo University (JP)
Corresponding author
Nakaki, Toshio
ORCID
Aoyama, Koji
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2013-10-18
Volume
14
Issue
10
Pages
21021-21044
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms141021021
PMC
PMC3821656
OpenAlex
W1989041767
Cited by
226
References
5
Citations by year
2026: 17 · 2025: 12 · 2024: 11 · 2023: 26 · 2022: 23 · 2021: 26 · 2020: 25 · 2019: 24 · 2018: 11 · 2017: 11 · 2016: 13 · 2015: 13 · 2014: 13
FWCI
1.19
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
Funders
Japan Society for the Promotion of Science (24590333, 23500454)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
glutathione, glutathione synthesis, neurodegeneration, oxidative stress, antioxidant defense, redox homeostasis, inborn errors of metabolism, neuroprotection
MeSH terms
Animals, Antioxidants, Glutathione, Humans, Oxidation-Reduction, Oxidative Stress, Neurodegenerative Diseases

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