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

作者：Silvia Olivera‐Bravo, César Augusto João Ribeiro, Eugenia Isasi, Emiliano Trías, Guilhian Leipnitz, Pablo Díaz‐Amarilla, Michael Woontner, Cheryl Tatano Beck, Stephen I. Goodman, Diogo O. Souza, Moaçir Wajner, Luis Barbeito · 发表于：Human Molecular Genetics · 年份：2015 · DOI：10.1093/hmg/ddv175 · 被引用次数：32 · 研究领域：Metabolism and Genetic Disorders、Mitochondrial Function and Pathology、Biochemical and Molecular Research

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 neurotox...