title: Striatal neuronal death mediated by astrocytes from the Gcdh-/- mouse model of glutaric acidemia type I.
abstract: Glutaric acidemia type I (GA-I) is an inherited neurometabolic childhood disorder caused by defective activity of glutaryl CoA dehydrogenase (GCDH) which disturb lysine (Lys) and tryptophan catabolism leading to neurotoxic accumulation of glutaric acid (GA) and related metabolites. However, it remains unknown whether GA toxicity is due to direct effects on vulnerable neurons or mediated by GA-intoxicated astrocytes that fail to support neuron function and survival. As damaged astrocytes can also contribute to sustain high GA levels, we explored the ability of Gcdh-/- mouse astrocytes to produce GA and induce neuronal death when challenged with Lys. Upon Lys treatment, Gcdh-/- astrocytes synthetized and released GA and 3-hydroxyglutaric acid (3HGA). Lys and GA treatments also increased oxidative stress and proliferation in Gcdh-/- astrocytes, both prevented by antioxidants. Pretreatment with Lys also caused Gcdh-/- astrocytes to induce extensive death of striatal and cortical neurons when compared with milder effect in WT astrocytes. Antioxidants abrogated the neuronal death induced by astrocytes exposed to Lys or GA. In contrast, Lys or GA direct exposure on Gcdh-/- or WT striatal neurons cultured in the absence of astrocytes was not toxic, indicating that neuronal death is mediated by astrocytes. In summary, GCDH-defective astrocytes actively contribute to produce and accumulate GA and 3HGA when Lys catabolism is stressed. In turn, astrocytic GA production induces a neurotoxic phenotype that kills striatal and cortical neurons by an oxidative stress-dependent mechanism. Targeting astrocytes in GA-I may prompt the development of new antioxidant-based therapeutical approaches.
authors.affiliation: Neurobiología Celular y Molecular, IIBCE, Montevideo, CIP 11600, Uruguay.
authors.forename: Silvia
authors.initials: S
authors.lastname: Olivera-Bravo
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre CEP 900035-003 RS, Brazil.
authors.forename: César A J
authors.initials: CA
authors.lastname: Ribeiro
authors.affiliation: Neurobiología Celular y Molecular, IIBCE, Montevideo, CIP 11600, Uruguay.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Isasi
authors.affiliation: Neurobiología Celular y Molecular, IIBCE, Montevideo, CIP 11600, Uruguay.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Trías
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre CEP 900035-003 RS, Brazil.
authors.forename: Guilhian
authors.initials: G
authors.lastname: Leipnitz
authors.affiliation: Neurobiología Celular y Molecular, IIBCE, Montevideo, CIP 11600, Uruguay.
authors.forename: Pablo
authors.initials: P
authors.lastname: Díaz-Amarilla
authors.affiliation: School of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Woontner
authors.affiliation: School of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Beck
authors.affiliation: School of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Goodman
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre CEP 900035-003 RS, Brazil.
authors.forename: Diogo
authors.initials: D
authors.lastname: Souza
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre CEP 900035-003 RS, Brazil, Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre, Porto Alegre CEP 900035-003 RS, Brazil and.
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
authors.affiliation: Institut Pasteur Montevideo, Mataojo 2020, Montevideo CIP 11400, Uruguay barbeito@pasteur.edu.uy.
authors.forename: Luis
authors.initials: L
authors.lastname: Barbeito
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001928:Brain Diseases, Metabolic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology
chemical_list: D050770:Glutaryl-CoA Dehydrogenase