NEUROPATHOPHYSIOLOGICAL MECHANISMS IN GLUTARIC ACIDURIA TYPE I: 3-HYDROXYGLUTARIC ACID LEADS TO AMMONIA INCREASE AND NON-APOPTOTIC CELL DEATH
Détails
ID Serval
serval:BIB_05EE0CA5A38E
Type
Actes de conférence (partie): contribution originale à la littérature scientifique, publiée à l'occasion de conférences scientifiques, dans un ouvrage de compte-rendu (proceedings), ou dans l'édition spéciale d'un journal reconnu (conference proceedings).
Sous-type
Poster: résume de manière illustrée et sur une page unique les résultats d'un projet de recherche. Les résumés de poster doivent être entrés sous "Abstract" et non "Poster".
Collection
Publications
Institution
Titre
NEUROPATHOPHYSIOLOGICAL MECHANISMS IN GLUTARIC ACIDURIA TYPE I: 3-HYDROXYGLUTARIC ACID LEADS TO AMMONIA INCREASE AND NON-APOPTOTIC CELL DEATH
Titre de la conférence
Annual Symposium of the Society for the Study of Inborn Errors of Metabolism
Adresse
Birmingham, United Kingdom, September 4-7, 2012
ISBN
0141-8955
Statut éditorial
Publié
Date de publication
2012
Volume
35
Série
Journal of Inherited Metabolic Diseases
Pages
S56
Langue
anglais
Notes
Document Type:Meeting Abstract
Résumé
A 3D in vitro model of rat organotypic brain cell cultures in aggregates was
used to investigate neurotoxicity mechanisms in glutaric aciduria type I
(GA-I). 1 mM glutarate (GA) or 3-hydroxyglutarate (3OHGA) were repeatedly
added to the culture media at two different time points. In cultures
treated with 3OHGA, we observed an increase in lactate in the medium,
pointing to a possible inhibition of Krebs cycle and respiratory chain. We
further observed that 3OHGA and to a lesser extend GA induced an
increase in ammonia production with concomitant decrease of glutamine
concentrations, which may suggest an inhibition of the astrocytic enzyme
glutamine synthetase. These previously unreported findings may uncover a
pathogenic mechanism in this disease which has deleterious effects on early
stages of brain development. By immunohistochemistry we showed that
3OHGA increased non-apoptotic cell death. On the cellular level, 3OHGA
and to a lesser extend GA led to cell swelling and loss of astrocytic fibers
whereas a loss of oligodendrocytes was only observed for 3OHGA. We
conclude that 3OHGAwas the most toxic metabolite in our model for GA-I.
3OHGA induced deleterious effects on glial cells, an increase of ammonia
production, and resulted in accentuated cell death of non-apoptotic origin.
used to investigate neurotoxicity mechanisms in glutaric aciduria type I
(GA-I). 1 mM glutarate (GA) or 3-hydroxyglutarate (3OHGA) were repeatedly
added to the culture media at two different time points. In cultures
treated with 3OHGA, we observed an increase in lactate in the medium,
pointing to a possible inhibition of Krebs cycle and respiratory chain. We
further observed that 3OHGA and to a lesser extend GA induced an
increase in ammonia production with concomitant decrease of glutamine
concentrations, which may suggest an inhibition of the astrocytic enzyme
glutamine synthetase. These previously unreported findings may uncover a
pathogenic mechanism in this disease which has deleterious effects on early
stages of brain development. By immunohistochemistry we showed that
3OHGA increased non-apoptotic cell death. On the cellular level, 3OHGA
and to a lesser extend GA led to cell swelling and loss of astrocytic fibers
whereas a loss of oligodendrocytes was only observed for 3OHGA. We
conclude that 3OHGAwas the most toxic metabolite in our model for GA-I.
3OHGA induced deleterious effects on glial cells, an increase of ammonia
production, and resulted in accentuated cell death of non-apoptotic origin.
Web of science
Création de la notice
14/02/2014 17:22
Dernière modification de la notice
20/08/2019 12:28
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