Structural and Functional Studies on Glutamate Decarboxylase.

这项建议旨在确定谷氨酸脱羧酶的两种已知亚型(GAD65和GAD67)的分子结构。GAD是一种人体必需的酶，负责合成主要的抑制性神经递质伽马氨基丁酸(GABA)。GABA在人类中枢神经系统(CNS)中起着抑制兴奋信号的作用。适当控制GABA合成是重要的，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。作为这一作用的结果，许多常见的疗法(例如苯二氮卓类药物)以涉及GABA神经递质系统的蛋白质为靶标。这项提议的目的是利用GAD的分子结构来了解如何实现对GABA生产的精细控制。除了在中枢神经系统中的作用外，GAD还是一种重要的人类自身抗原。GAD的一种亚型GAD65的抗体存在于大多数I型糖尿病患者以及某些运动障碍僵硬综合征和相关中枢神经系统疾病的患者中。提示自身抗体的产生可能在这些疾病的病理生理学中起关键作用。尽管与GAD65有80%的序列相似性，但对GAD的另一种亚型GAD67的自身抗体在疾病患者中很少发现。这项资助的目的是描述自身抗体所针对的GAD区域的特征。这些数据将使我们了解为什么某些自身抗体能够抑制GAD酶活性，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.