Structural and Functional Studies on Glutamate Decarboxylase.

本研究旨在确定谷氨酸脱羧酶（GAD65和GAD67）的两种已知亚型的分子结构。GAD是一种人体必需的酶，负责合成初级抑制性神经递质γ -氨基丁酸（GABA）。GABA在人类中枢神经系统（CNS）中起抑制兴奋信号的作用。适当控制GABA的合成是很重要的，GABA水平的紊乱是人类疾病如顽固性癫痫、抑郁症和精神分裂症的原因。由于这一作用，许多常见的治疗药物（例如苯二氮卓类药物）靶向GABA神经递质系统中涉及的蛋白质。本课题的目标是利用GAD的分子结构来了解如何实现对GABA产生的精细控制。GAD除了在中枢神经系统中发挥作用外，还是一种重要的人类自身抗原。在大多数I型糖尿病患者以及某些患有运动障碍僵硬人综合征和中枢神经系统相关疾病的患者中发现了GAD的一种亚型GAD65的抗体。这表明，自身抗体的发展可能在这些疾病的病理生理中起关键作用。尽管与GAD65具有80%的序列相似性，但在患者中很少发现针对另一种GAD亚型GAD67的自身抗体。这项资助的目的是表征自身抗体靶向的广泛性焦虑症区域。这些数据将使我们理解为什么某些自身抗体能够抑制GAD酶的活性，以及为什么GAD65而不是GAD67被自身抗体识别。

This proposal aims to determine the molecular structure of the two known isoforms of Glutamate Decarboxylase (GAD65 and GAD67). GAD in an essential human enzyme that is responsible for synthesising the primary inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GABA functions in the human Central Nervous System (CNS) to dampen down excitatory signals. Proper control of GABA synthesis is important and perturbations in GABA levels lies behind human diseases such as intractable epilepsy, depression and schizophrenia. As a result of this role, numerous common therapeutics (for example benzodiazepines) target proteins involved in the GABA neurotransmitter system. The goal of this proposal is to use the molecular structures of GAD to understand how to achieve fine control of GABA production. In addition to its role in the CNS, GAD is an important human autoantigen. Antibodies to one isoform of GAD, GAD65, are found in most patients with type I diabetes as well as certain patients with the movement disorder stiff person syndrome and related diseases of the CNS. It is suggested that the development of auto-antibodies may play a key role in the pathophysiology of these conditions. Despite sharing >80% sequence similarity with GAD65, autoantibodies to the other isoform of GAD, GAD67, are rarely found in patients with disease. The aim of this grant is to characterise the region of GAD that is targetted by autoantibodes. These data will allow us to understand why certain autoantibodes are able to inhibit GAD enzyme activity and why GAD65, but not GAD67 is recognised by autoantibodes.