GLUTAMIC DEHYDROGENASE IN NEUROLOGIC DISORDERS

我们实验室最近的研究表明，部分缺乏 谷氨酸脱氢酶(GDH)和谷氨酸代谢异常 一种隐性遗传性遗传病的特异性生化缺陷 橄榄桥小脑萎缩(OPCA)。更多的研究揭示了证据 人类白细胞中存在两种不同形式的谷氨酸脱氢酶 和成纤维细胞，以及在大鼠脑中。一种同工酶，即 “可溶性”，耐高温(在47.5℃)，其中作为另一同工酶， 它是“颗粒状”的，不耐热(在47.5摄氏度)。两者的确定 隐性OPCa患者白细胞GDH同工酶的研究 完全缺乏耐热的葡萄糖脱氢酶。这些结果强烈地表明 热敏性谷氨酸甘油脱氢酶的缺乏才是真正的基因缺陷。 隐性OPCA的形式。我们建议：(1)延长现行的 人血白细胞两种谷氨酸脱氢酶同工酶活性的研究 OPCA患者以及其他退行性神经疾病患者 以进一步巩固我们关于与 谷氨酸脱氢酶缺乏。(2)调查是否存在 在培养的皮肤成纤维细胞中也存在热敏性谷氨酸脱氢酶。 病人。(3)测定两种谷氨酸脱氢酶同工酶的活性。 专性杂合子的白细胞和培养的皮肤成纤维细胞 (GDH缺陷患者的父母和子女)。(4)净化大鼠 以及人脑和肝脏的GDH同工酶，并比较它们的性质。 (5)进一步鉴定白细胞中的谷氨酸脱氢酶同工酶和 来自患者和对照组的成纤维细胞，并开发改进的方法 他们的分离。(六)拓展现有的系统代谢研究 谷氨酸脱氢酶缺乏症患者和其他疾病患者的谷氨酸水平 退行性神经疾病。(七)进一步探索 支链氨基酸等谷氨酸脱氢酶激动剂在体内的作用 阻断或逆转谷氨酸脱氢酶缺陷神经病的病程 精神错乱。

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.