Tabrizi S J, Cleeter M W, Xuereb J, Taanman J W, Cooper J M, Schapira A H
University Department of Clinical Neurosciences, Royal Free and UCH School of Medicine, London, UK.
Ann Neurol. 1999 Jan;45(1):25-32. doi: 10.1002/1531-8249(199901)45:1<25::aid-art6>3.0.co;2-e.
The physiological role of huntingtin and the mechanisms by which the expanded CAG repeat in ITI5 and its polyglutamine stretch in mutant huntingtin induce Huntington's disease (HD) are unknown. Several techniques have now demonstrated abnormal metabolism in HD brain; direct measurement of respiratory chain enzyme activities has shown severe deficiency of complex II/III and a milder defect of complex IV. We confirm that these abnormalities appear to be confined to the striatum within the HD brain. Analysis of complex II/III activity in HD fibroblasts was normal, despite expression of mutant huntingtin. Although glyceraldehyde 3-phosphate dehydrogenase (a huntingtin binding protein) activity was normal in all areas studied, aconitase activity was decreased to 8% in HD caudate, 27% in putamen, and 52% in cerebral cortex, but normal in HD cerebellum and fibroblasts. We have demonstrated that although complexes II and III are those parts of the respiratory chain most vulnerable to inhibition in the presence of a nitric oxide (NO*) generator, aconitase activity was even more sensitive to inhibition. The pattern of these enzyme deficiencies and their parallel to the anatomical distribution of HD pathology support an important role for NO* and excitotoxicity in HD pathogenesis. Furthermore, based on the biochemical defects we have described, we suggest that NO* generation produces a graded response, with aconitase inhibition followed by complex II/III inhibition and the initiation of a self-amplifying cycle of free radical generation and aconitase inhibition, which results in severe ATP depletion. We propose that these events are important in determining neuronal cell death and are critical steps in the pathogenesis of HD.
亨廷顿蛋白的生理作用以及 ITI5 基因中 CAG 重复序列的扩增及其在突变型亨廷顿蛋白中的多聚谷氨酰胺延伸导致亨廷顿舞蹈症（HD）的机制尚不清楚。目前有几种技术已证明 HD 患者大脑存在代谢异常；对呼吸链酶活性的直接测量显示，复合物 II/III 严重缺乏，复合物 IV 存在较轻微的缺陷。我们证实，这些异常似乎局限于 HD 患者大脑的纹状体中。尽管存在突变型亨廷顿蛋白的表达，但对 HD 成纤维细胞中复合物 II/III 活性的分析结果正常。虽然在所研究的所有区域中甘油醛 - 3 - 磷酸脱氢酶（一种亨廷顿蛋白结合蛋白）的活性正常，但乌头酸酶活性在 HD 患者的尾状核中降至 8%，壳核中降至 27%，大脑皮层中降至 52%，而在 HD 患者的小脑和成纤维细胞中则正常。我们已经证明，尽管复合物 II 和 III 是呼吸链中在一氧化氮（NO*）生成剂存在下最易受到抑制的部分，但乌头酸酶活性对抑制更为敏感。这些酶缺陷的模式及其与 HD 病理解剖分布的平行关系支持了 NO和兴奋性毒性在 HD 发病机制中的重要作用。此外，基于我们所描述的生化缺陷，我们认为 NO的产生会产生一种分级反应，先是乌头酸酶受到抑制，随后是复合物 II/III 受到抑制，并引发自由基生成和乌头酸酶抑制的自我放大循环，这会导致严重的 ATP 耗竭。我们提出这些事件在决定神经元细胞死亡中很重要，并且是 HD 发病机制中的关键步骤。
