Ammonium accumulation and chemokine decrease in culture media of Gcdh<sup>-/-</sup> 3D reaggregated brain cell cultures.

Details

Serval ID
serval:BIB_27B1944B46C3
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Ammonium accumulation and chemokine decrease in culture media of Gcdh<sup>-/-</sup> 3D reaggregated brain cell cultures.
Journal
Molecular genetics and metabolism
Author(s)
Cudré-Cung H.P., Remacle N., do Vale-Pereira S., Gonzalez M., Henry H., Ivanisevic J., Schmiesing J., Mühlhausen C., Braissant O., Ballhausen D.
ISSN
1096-7206 (Electronic)
ISSN-L
1096-7192
Publication state
Published
Issued date
04/2019
Peer-reviewed
Oui
Volume
126
Number
4
Pages
416-428
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Glutaric Aciduria type I (GA-I) is caused by mutations in the GCDH gene. Its deficiency results in accumulation of the key metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body tissues and fluids. Present knowledge on the neuropathogenesis of GA-I suggests that GA and 3-OHGA have toxic properties on the developing brain. We analyzed morphological and biochemical features of 3D brain cell aggregates issued from Gcdh <sup>-/-</sup> mice at two different developmental stages, day-in-vitro (DIV) 8 and 14, corresponding to the neonatal period and early childhood. We also induced a metabolic stress by exposing the aggregates to 10 mM l-lysine (Lys). Significant amounts of GA and 3-OHGA were detected in Gcdh <sup>-/-</sup> aggregates and their culture media. Ammonium was significantly increased in culture media of Gcdh <sup>-/-</sup> aggregates at the early developmental stage. Concentrations of GA, 3-OHGA and ammonium increased significantly after exposure to Lys. Gcdh <sup>-/-</sup> aggregates manifested morphological alterations of all brain cell types at DIV 8 while at DIV 14 they were only visible after exposure to Lys. Several chemokine levels were significantly decreased in culture media of Gcdh <sup>-/-</sup> aggregates at DIV 14 and after exposure to Lys at DIV 8. This new in vitro model for brain damage in GA-I mimics well in vivo conditions. As seen previously in WT aggregates exposed to 3-OHGA, we confirmed a significant ammonium production by immature Gcdh <sup>-/-</sup> brain cells. We described for the first time a decrease of chemokines in Gcdh <sup>-/-</sup> culture media which might contribute to brain cell injury in GA-I.
Keywords
Amino Acid Metabolism, Inborn Errors/genetics, Ammonium Compounds/analysis, Ammonium Compounds/metabolism, Animals, Brain/cytology, Brain/drug effects, Brain/pathology, Brain Diseases, Metabolic/genetics, Cell Culture Techniques, Chemokines/analysis, Chemokines/metabolism, Culture Media/analysis, Culture Media/metabolism, Glutaryl-CoA Dehydrogenase/deficiency, Glutaryl-CoA Dehydrogenase/genetics, Lysine/pharmacology, Mice, Mice, Inbred C57BL, Mice, Knockout, Tissue Scaffolds, Ammonium, Brain, Chemokines, Glutaric aciduria type I, Lysine
Pubmed
Web of science
Create date
18/02/2019 15:52
Last modification date
16/11/2019 7:16
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