Glutamate dehydrogenase in spinocerebellar degeneration.

脊髓小脑变性是一种异质性疾病，其发病机制和病因尚不清楚。我们已经证实，四名患者的白细胞和/或成纤维细胞中的谷氨酸脱氢酶(GDH)活性降低。其中3例表现为进行性小脑功能障碍和其他体征，包括皮质脊髓、眼球运动功能障碍和周围神经病变。其中一例表现为不典型的帕金森氏症。我们的实验就是为了这两个目的而进行的。首先，研究了白细胞内谷氨酸脱氢酶降低的机制。我们建立了测定白细胞中GDH蛋白含量的放射免疫法。4例患者蛋白质含量均降低，其比值与酶活性成正比。在正常对照组、疾病对照组和GDH缺乏症患者中，GDH特异性活性是一致的。这些结果表明，GdH的降低不是由于结构的变化导致质变，而是由于GdH蛋白的减少。目前对谷氨酸脱氢酶蛋白的加工过程的研究还在进行中，以考察谷氨酸脱氢酶的生物合成途径受到影响的可能性。其次，试图了解GDH缺陷是否是细胞死亡的致病因素。与正常对照组相比，培养的成纤维细胞对高浓度的L-谷氨酸敏感。这些细胞在24小时内出现变性和活力丧失。所有这些结果表明，这些病例存在全身性GDH活性异常，GDH介导过程中的代谢障碍对细胞是致病的，可能是神经细胞。

Spinocerebellar degeneration is a heterogeneous diseas complex and its pathogenesis and etiology are completely unknown. We have confirmed that glutamate dehydrogenase (GDH) activity is reduced in leukocytes and /or fibroblasts from four patients. Three of them manifested progressive cerebellar dysfunction and additional signs including corticospinal, oculomotor dysfunctions and peripheral neuropathy. The one showed atypical parkinsonism. Our experiments were made for the two purposes. Firstly, the mechanism by which GDH was reduced in leukocytes was studied. We established the radioimmunoassay for the determination of GDH protein contents in leukocytes. The protein content was decreased in the four patients and its ration was proportional to the enzyme activity. The GDH specific activity was consistent in normal controls, diseased controls, and patients with GDH deficiency. These results showed that the reduction of GDH was not due to the structural changes leading to qualitative changes but due to decreased GDH protein. The study of the processing of GDH protein is underprogress in order to examine the possibility that biosynthetic pathway of GDH is affected. The secondly, an attempt was made to see whether GDH deficit was pathogenic for cell death. The cultured fibroblasts had a sensitivity to a high concentrations of L-glutamate compared to normal controls. These cells showed degeneration and lossof viability within 24 hrs. All these results suggested that the cases presented here had the systemic abnormality of GDH activity, and impaired metabolism in GDH mediated process was pathogenic for the cell, possibly neuronal cells.