Ammonium accumulation and cell death in a rat 3D brain cell model of glutaric aciduria type I.

Détails

Ressource 1Télécharger: BIB_0D885DAC320F.P001.pdf (4622.67 [Ko])
Etat: Serval
Version: de l'auteur
ID Serval
serval:BIB_0D885DAC320F
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Ammonium accumulation and cell death in a rat 3D brain cell model of glutaric aciduria type I.
Périodique
Plos One
Auteur(s)
Jafari P., Braissant O., Zavadakova P., Henry H., Bonafé L., Ballhausen D.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Statut éditorial
Publié
Date de publication
2013
Peer-reviewed
Oui
Volume
8
Numéro
1
Pages
e53735
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Résumé
Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency) is an inborn error of metabolism that usually manifests in infancy by an acute encephalopathic crisis and often results in permanent motor handicap. Biochemical hallmarks of this disease are elevated levels of glutarate and 3-hydroxyglutarate in blood and urine. The neuropathology of this disease is still poorly understood, as low lysine diet and carnitine supplementation do not always prevent brain damage, even in early-treated patients. We used a 3D in vitro model of rat organotypic brain cell cultures in aggregates to mimic glutaric aciduria type I by repeated administration of 1 mM glutarate or 3-hydroxyglutarate at two time points representing different developmental stages. Both metabolites were deleterious for the developing brain cells, with 3-hydroxyglutarate being the most toxic metabolite in our model. Astrocytes were the cells most strongly affected by metabolite exposure. In culture medium, we observed an up to 11-fold increase of ammonium in the culture medium with a concomitant decrease of glutamine. We further observed an increase in lactate and a concomitant decrease in glucose. Exposure to 3-hydroxyglutarate led to a significantly increased cell death rate. Thus, we propose a three step model for brain damage in glutaric aciduria type I: (i) 3-OHGA causes the death of astrocytes, (ii) deficiency of the astrocytic enzyme glutamine synthetase leads to intracerebral ammonium accumulation, and (iii) high ammonium triggers secondary death of other brain cells. These unexpected findings need to be further investigated and verified in vivo. They suggest that intracerebral ammonium accumulation might be an important target for the development of more effective treatment strategies to prevent brain damage in patients with glutaric aciduria type I.
Pubmed
Web of science
Open Access
Oui
Création de la notice
15/02/2013 12:34
Dernière modification de la notice
08/05/2019 14:23
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