title: Ammonium accumulation and cell death in a rat 3D brain cell model of glutaric aciduria type I.
abstract: 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.
authors: Inborn Errors of Metabolism, Molecular Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
authors: Paris
authors: P
authors: Jafari
authors: Olivier
authors: O
authors: Braissant
authors: Petra
authors: P
authors: Zavadakova
authors: Hugues
authors: H
authors: Henry
authors: Luisa
authors: L
authors: Bonafé
authors: Diana
authors: D
authors: Ballhausen
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D001928:Brain Diseases, Metabolic / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D003470:Culture Media / Q000737:chemistry; D004195:Disease Models, Animal; D005977:Glutarates / Q000494:pharmacology; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000644:Quaternary Ammonium Compounds / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C108959:3-hydroxyglutaric acid; D003470:Culture Media; D005977:Glutarates; D000644:Quaternary Ammonium Compounds; D050770:Glutaryl-CoA Dehydrogenase