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首页> 外文期刊>The European Journal of Neuroscience >NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d-2-hydroxyglutaric aciduria.
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NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d-2-hydroxyglutaric aciduria.

机译：NMDA受体激活和呼吸链复合物V抑制导致d-2-羟基戊二酸尿症的神经退行性变。

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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.
机译：遗传的神经代谢疾病d-2-羟基戊二酸尿症在婴儿期和幼儿期易受伤害的大脑区域进行性神经退行性变，并经常表现为肌张力低下，癫痫和精神运动迟缓。在这里，我们报告内源性积累的代谢物d-2-羟基谷氨酸（D-2）的致病作用，其结构类似于兴奋性氨基酸谷氨酸，是由至少三种机制介导的。 （i）在鸡和大鼠的原代神经元培养物中，D-2-诱导的兴奋毒性细胞损伤涉及N-甲基-d-天冬氨酸（NMDA）受体激活。实际上，D-2激活了HEK293细胞中的重组NMDA受体（NR1 / NR2A，NR1 / NR2B），但未激活重组α-氨基-3-羟基-5-甲基-4-异恶唑（AMPA）受体。 （ii）使用呋喃2作为钙指示剂和对氧化剂敏感的染料dihydrorhodamine-123的荧光显微镜显示D-2干扰了细胞内钙稳态，并引发了活性氧的产生。 （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ATP合成的抑制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通过众所周知的谷氨酸，NMDA或线粒体毒素的机制刺激神经变性。总之，兴奋性毒性促进d-2-羟基戊二酸尿症的神经病理学，突出了新的神经保护策略。

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