Dissociation of AGAT, GAMT and SLC6A8 in CNS: Relevance to creatine deficiency syndromes
Open accessAbstract
AGAT and GAMT, the two enzymes of the creatine synthesis pathway, are well expressed within CNS, suggesting autonomous brain creatine synthesis. This contradicts SLC6A8 deficiency, which causes creatine deficiency despite CNS expression of AGAT and GAMT. We hypothesized that AGAT and GAMT were not co-expressed by brain cells, and that guanidinoacetate must be transported between cells to allow creatine synthesis. We finely analyzed the cell-to-cell co-expression of AGAT, GAMT and SLC6A8 in various regions of rat CNS, and showed that in most structures, cells co-expressing AGAT+GAMT (equipped for autonomous creatine synthesis) were in low proportions (<20%). Using reaggregating brain cell cultures, we also showed that brain cells take up guanidinoacetate and convert it to creatine. Guanidinoacetate uptake was competed by creatine. This suggests that in most brain regions, guanidinoacetate is transported from AGAT- to GAMT-expressing cells through SLC6A8 to allow creatine synthesis, thereby explaining creatine deficiency in SLC6A8-deficient CNS.
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Some individuals have creatine synthesis deficiencies due to inborn errors in AGAT, GAMT and/or CRTR deficiencies and therefore must depend on dietary creatine intake to maintain normal muscle and brain concentrations of PCr and Cr.
“Some individuals have been found to have creatine synthesis deficiencies due to inborn errors in AGAT, GMAT and/or creatine transporter (CRTR) deficiencies and therefore must depend on dietary creatine intake in order to maintain normal muscle and brain concentrations of PCr and Cr”
From International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine (2017) · cites this paper as [15]
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“It suggests that these neuronal layers permanently need high Cr levels, in line with their high creatine kinase activity (Wallimann and Hemmer, 1994; Kaldis et al., 1996).”
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Self-citationPhenotype and genotype in 101 males with X-linked creatine transporter deficiency
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Self-citationCyclocreatine treatment improves cognition in mice with creatine transporter deficiency
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Self-citationLong-term follow-up and treatment in nine boys with X-linked creatine transporter defect
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- Authors
- Braissant, O., Béard, E., Torrent, C., & Henry, H.
- Affiliations
- Centre Hospitalier Universitaire Vaudois (CH)
- Corresponding author
- Braissant, Olivier
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2010-02
- Volume
- 37
- Issue
- 2
- Pages
- 423-433
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W2024955227
- Cited by
- 94
- References
- 3
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 7 · 2023: 12 · 2022: 4 · 2021: 8 · 2020: 5 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 6 · 2015: 5 · 2014: 7 · 2013: 7 · 2012: 7
- FWCI
- 3.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion, other-oa)
- IRIS (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (3100A0-100778, 3100A0-116859)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- creatine deficiency syndrome, arginine:glycine amidinotransferase, GAMT, SLC6A8, guanidinoacetic acid, creatine synthesis, central nervous system
- MeSH terms
- Amidinotransferases, Animals, Brain Mapping, Cell Count, Cells, Cultured, Central Nervous System, Creatine, Glycine, Immunohistochemistry, Nerve Tissue Proteins, Neurons, RNA, Messenger, Syndrome, Rats, Sprague-Dawley, In Situ Hybridization, Brain Diseases, Metabolic, Inborn, Plasma Membrane Neurotransmitter Transport Proteins, Guanidinoacetate N-Methyltransferase, Rats
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