Striatal neuronal death mediated by astrocytes from the Gcdh-/- mouse model of glutaric acidemia type I

• Published in: Human molecular genetics 2015-08, Vol.24 (16), p.4504-4515
• Main Authors: Olivera-Bravo, Silvia, Ribeiro, César A J, Isasi, Eugenia, Trías, Emiliano, Leipnitz, Guilhian, Díaz-Amarilla, Pablo, Woontner, Michael, Beck, Cheryl, Goodman, Stephen I, Souza, Diogo, Wajner, Moacir, Barbeito, Luis
• Format: Article
• Language: English
• Subjects: Amino Acid Metabolism, Inborn Errors - genetics; Amino Acid Metabolism, Inborn Errors - metabolism; Amino Acid Metabolism, Inborn Errors - pathology; Animals; Astrocytes - metabolism; Astrocytes - pathology; Brain Diseases, Metabolic - genetics; Brain Diseases, Metabolic - metabolism; Brain Diseases, Metabolic - pathology; Cell Survival - genetics; Corpus Striatum - metabolism; Corpus Striatum - pathology; Disease Models, Animal; Glutaryl-CoA Dehydrogenase - deficiency; Glutaryl-CoA Dehydrogenase - genetics; Glutaryl-CoA Dehydrogenase - metabolism; Humans; Mice; Mice, Knockout; Neurons - metabolism; Neurons - pathology
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddv175

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.