4 research outputs found
Parallel Metabolomics and Lipidomics of a PSMA/GCPII Deficient Mouse Model Reveal Alteration of NAAG Levels and Brain Lipid Composition
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-γ-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
Parallel Metabolomics and Lipidomics of a PSMA/GCPII Deficient Mouse Model Reveal Alteration of NAAG Levels and Brain Lipid Composition
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-γ-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
Parallel Metabolomics and Lipidomics of a PSMA/GCPII Deficient Mouse Model Reveal Alteration of NAAG Levels and Brain Lipid Composition
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-γ-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
Parallel Metabolomics and Lipidomics of a PSMA/GCPII Deficient Mouse Model Reveal Alteration of NAAG Levels and Brain Lipid Composition
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-γ-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