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
Neurobiología Celular y Molecular, IIBCE, Montevideo, CIP 11600, Uruguay.
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre CEP 900035-003 RS, Brazil.
Hum Mol Genet. 2015 Aug 15;24(16):4504-15. doi: 10.1093/hmg/ddv175. Epub 2015 May 12.
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.
I型戊二酸血症（GA-I）是一种遗传性儿童神经代谢疾病，由戊二酰辅酶A脱氢酶（GCDH）活性缺陷引起，该缺陷扰乱了赖氨酸（Lys）和色氨酸的分解代谢，导致戊二酸（GA）及相关代谢产物的神经毒性蓄积。然而，GA毒性是由于对易损神经元的直接作用，还是由未能支持神经元功能和存活的GA中毒星形胶质细胞介导，仍不清楚。由于受损的星形胶质细胞也可能导致GA水平持续升高，我们研究了Gcdh-/-小鼠星形胶质细胞在受到Lys刺激时产生GA并诱导神经元死亡的能力。用Lys处理后，Gcdh-/-星形胶质细胞合成并释放了GA和3-羟基戊二酸（3HGA）。Lys和GA处理还增加了Gcdh-/-星形胶质细胞的氧化应激和增殖，抗氧化剂可预防这两种情况。与野生型（WT）星形胶质细胞的较轻影响相比，用Lys预处理还导致Gcdh-/-星形胶质细胞诱导纹状体和皮质神经元广泛死亡。抗氧化剂消除了暴露于Lys或GA的星形胶质细胞诱导的神经元死亡。相比之下，在没有星形胶质细胞的情况下，Lys或GA直接暴露于Gcdh-/-或WT纹状体神经元无毒，表明神经元死亡是由星形胶质细胞介导的。总之，当Lys分解代谢受到压力时，GCDH缺陷的星形胶质细胞积极参与GA和3HGA的产生和蓄积。反过来，星形胶质细胞产生的GA诱导一种神经毒性表型，通过氧化应激依赖性机制杀死纹状体和皮质神经元。针对GA-I中的星形胶质细胞可能会促进基于抗氧化剂的新治疗方法的开发。
