NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in D-2-hydroxyglutaric aciduria
NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in D-2-hydroxyglutaric aciduria
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DOI：
10.1046/j.1460-9568.2002.02055.x
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发表时间：
2002-07-01
影响因子：
3.4
通讯作者：
Köhr, G
中科院分区：
文献类型：
--
作者：
Kölker, S;Pawlak, V;Köhr, G
遗传性神经代谢疾病D-2-羟基谷物酸尿症使脆弱的大脑区域的进行性神经退行性在婴儿期和幼儿期的进行性神经退行性复杂化，经常出现低骨，癫痫和心理抑制作用。在这里，我们报告说，内源性积累的代谢物D-2-羟基戊二酸（D-2）的致病作用在结构上与兴奋性氨基酸谷氨酸的结构相似，至少是由三种机制介导的。 （i）D-2诱导的鸡和大鼠原发性神经元培养物中的兴奋性细胞损伤涉及N-甲基-D-天冬氨酸（NMDA）受体激活。实际上，D-2激活的重组NMDA受体（NR1/NR2A，NR1/NR2B），但不是HEK293细胞中的重组α-Amino-3-羟基-3-羟基-5-甲基-4-偶氮-4-偶氮唑（AMPA）受体。 （ii）使用FURA-2作为钙指标的荧光显微镜，氧化剂敏感的染料二氢hodamine-123表明，D-2扰乱了细胞内钙稳态，并引起了反应性氧。 （iii）D-2降低了线粒体呼吸链的复合物V（ATP合酶）活性，反映了由于抑制ATP而导致的能量代谢受损，但没有影响电子转移复合物I-IV。因此，D-2通过谷氨酸，NMDA或线粒体毒素而闻名的机制刺激神经退行性。总之，兴奋性毒性有助于D-2-羟基氯丁胺酸的神经病理学，突出了新的神经保护策略。
The inherited neurometabolic disease d-2-hydroxyglutaric aciduria is complicated by progressive neurodegeneration of vulnerable brain regions during infancy and early childhood, frequently presenting with hypotonia, epilepsy and psychomotor retardation. Here, we report that the pathogenetic role of the endogenously accumulating metabolite d-2-hydroxyglutarate (D-2), which is structurally similar to the excitatory amino acid glutamate, is mediated by at least three mechanisms. (i) D-2-induced excitotoxic cell damage in primary neuronal cultures from chick and rat involved N -methyl-d-aspartate (NMDA) receptor activation. Indeed, D-2 activated recombinant NMDA receptors (NR1/NR2A, NR1/NR2B) but not recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptors in HEK293 cells. (ii) Fluorescence microscopy using fura-2 as a calcium indicator and the oxidant-sensitive dye dihydrorhodamine-123 revealed that D-2 disturbed intracellular calcium homeostasis and elicited the generation of reactive oxygen species. (iii) D-2 reduced complex V (ATP synthase) activity of the mitochondrial respiratory chain, reflecting an impaired energy metabolism due to inhibition of ATP synthesis but without affecting the electron-transferring complexes I-IV. Thus, D-2 stimulates neurodegeneration by mechanisms well-known for glutamate, NMDA or mitochondrial toxins. In conclusion, excitotoxicity contributes to the neuropathology of d-2-hydroxyglutaric aciduria, highlighting new neuroprotective strategies.