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Parallel Metabolomics and Lipidomics of a PSMA/GCPII Deficient Mouse Model Reveal Alteration of NAAG Levels and Brain Lipid Composition
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SYSNO ASEP 0583976 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Parallel Metabolomics and Lipidomics of a PSMA/GCPII Deficient Mouse Model Reveal Alteration of NAAG Levels and Brain Lipid Composition Author(s) Sedlák, František (UOCHB-X) RID, ORCID
Kvasnička, A. (CZ)
Marešová, Barbora (UOCHB-X)
Brumarová, R. (CZ)
Dobešová, D. (CZ)
Dostálová, K. (CZ)
Šrámková, Karolína (UOCHB-X)
Pehr, Martin (UOCHB-X)
Šácha, Pavel (UOCHB-X) RID, ORCID
Friedecký, D. (CZ)
Konvalinka, Jan (UOCHB-X) RID, ORCIDSource Title ACS Chemical Neuroscience. - : American Chemical Society - ISSN 1948-7193
Roč. 15, č. 7 (2024), s. 1342-1355Number of pages 14 s. Language eng - English Country US - United States Keywords lipidomics ; metabolomics ; N-acetyl-aspartyl-glutamate ; glutamatecarboxypeptidase II ; folh1 ; folyl-poly-gamma-glutamylhydrolase I R&D Projects GA21-04166S GA ČR - Czech Science Foundation (CSF) LX22NPO5102 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 001168011200001 EID SCOPUS 85186104685 DOI 10.1021/acschemneuro.3c00494 Annotation Glutamate carboxypeptidase II (GCPII, also known as PSMA or FOLH1) is responsible for the cleavage of N-acetyl-aspartyl-glutamate (NAAG) to N-acetyl-aspartate and glutamate in the central nervous system and facilitates the intestinal absorption of folate by processing dietary folyl-poly-gamma-glutamate in the small intestine. The physiological function of GCPII in other organs like kidneys is still not known. GCPII inhibitors are neuroprotective in various conditions (e.g., ischemic brain injury) in vivo, however, their utilization as potential drug candidates has not been investigated in regard to not yet known GCPII activities. To explore the GCPII role and possible side effects of GCPII inhibitors, we performed parallel metabolomic and lipidomic analysis of the cerebrospinal fluid (CSF), urine, plasma, and brain tissue of mice with varying degrees of GCPII deficiency (fully deficient in Folh1,/-, one allele deficient in Folh1, +/-, and wild type, +/+). Multivariate analysis of metabolites showed no significant differences between wild-type and GCPII-deficient mice (except for NAAG), although changes were observed between the sex and age. NAAG levels were statistically significantly increased in the CSF, urine, and plasma of GCPII-deficient mice. However, no difference in NAAG concentrations was found in the whole brain lysate likely because GCPII, as an extracellular enzyme, can affect only extracellular and not intracellular NAAG concentrations. Regarding the lipidome, the most pronounced genotype-linked changes were found in the brain tissue. In brains of GCPII-deficient mice, we observed statistically significant enrichment in phosphatidylcholine-based lipids and reduction of sphingolipids and phosphatidylethanolamine plasmalogens. We hypothesize that the alteration of the NAA-NAAG axis by absent GCPII activity affected myelin composition. In summary, the absence of GCPII and thus similarly its inhibition do not have detrimental effects on metabolism, with just minor changes in the brain lipidome. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2025 Electronic address https://doi.org/10.1021/acschemneuro.3c00494
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