GLUTAMIC DEHYDROGENASE IN NEUROLOGIC DISORDERS

我们实验室最近的研究表明， 谷氨酸脱氢酶（GDH）和异常谷氨酸代谢是 一种隐性遗传的特殊生化缺陷 橄榄体桥脑小脑萎缩（OPCA）。 进一步的研究显示， 人白细胞中存在两种不同形式的GDH 和成纤维细胞以及大鼠大脑中的细胞。 一种同工酶， "可溶的"，是耐热的（在47.5 ℃），而作为另一种同工酶， 其为"颗粒状"，是热不稳定的（在47.5 ℃）。 两者的确定 隐性OPCA患者的白细胞中GDH同工酶显示， 不耐热GDH的完全缺乏。 这些结果有力地表明 热敏GDH的缺乏是这种基因的实际缺陷。 隐性OPCA的形式。 我们建议：（1）扩大现有的 本文报道了两种GDH同功酶活性的研究结果。 OPCA患者以及其他神经退行性疾病患者 疾病，以进一步巩固我们的表型相关的数据， GDH缺乏。 (2)为了调查是否存在 热敏感性GDH也存在于培养的皮肤成纤维细胞中， 患者 (3)为了评价两种GDH同工酶的活性， 白细胞和培养的皮肤成纤维细胞从义务杂合子 （GDH缺乏患者的父母和子女）。 (4)为了净化老鼠 以及人脑和肝GDH同工酶，并比较它们的性质。 (5)为了进一步表征白细胞中的GDH同工酶， 本发明的目的是开发用于从患者和对照中分离成纤维细胞的改进的方法， 他们的分离。 (6)拓展目前对全身代谢的研究 GDH缺乏症患者以及其他 退行性神经系统疾病 (7)为了进一步探索 GDH激活剂如支链氨基酸在 阻止或逆转GDH缺乏的神经系统疾病的进程， 紊乱

Recent studies in our laboratory revealed that a partial deficiency of glutamate dehydrogenase (GDH) and abnormal glutamate metabolism are specific biochemical defects of a form of recessively-inherited olivopontocerebellar atrophy (OPCA). Additional studies revealed evidence for the cellular presence of two distinct forms of GDH in human leukocytes and fibroblasts as well as in rat brain. One isoenzyme, which is "soluble", is heat resistant (at 47.5 C) where as the other isoenzyme, which is "particulate", is heat-labile (at 47.5 C). Determination of both GDH isoenzymes in leukocytes from patients with recessive OPCA revealed complete deficiency of the heatlabile GDH. These results strongly suggest that deficiency of the heat-sensitive GDH is the actual gene defect of this form of recessive OPCA. We propose: (1) To extend the current investigations on the activity of the two GDH isoenzymes in leukocytes from patients with OPCA as well as patients with other degenerative neurological disorders to further consolidate our data on the phenotype associated with GDH deficiency. (2) To investigate whether a deficiency of the heat-sensitive GDH is also present in cultured skin fibroblasts from these patients. (3) To evaluate the activities of the two GDH isoenzymes in leukocytes and cultured skin fibroblasts from obligated heterozygotes (parents and children of GDH-deficient patients). (4) To purify the rat and human brain and liver GDH isoenzymes and to compare their properties. (5) To further characterize the GDH isoenzymes in leukocytes and fibroblasts from patients and controls and to develop improved methods for their separation. (6) To expand the current studies on systemic metabolism of glutamate in patients with GDH deficiency as well as patients with other degenerative neurological disorders. (7) To further explore the possible role of GDH-activating agents such as the branched-chain amino acids in arresting or reversing the course of the GDH-deficient neurological disorders.