TRANSGLUTAMINASE AND DISEASES OF EXPANDED POLYGLUTAMINE

描述(摘自申请者摘要)：亨廷顿病和8 其他中枢神经系统疾病都是由一种含有 多聚谷氨酰胺的扩展序列。每种蛋白质通常都含有一个 聚谷氨酰胺序列不超过40个残基，但突变扩增 任何蛋白质中的这个序列都会导致神经元损伤和一种 相应的疾病。 如果可以准确地说明病因，那么发病机制就不能。一定是 解释了为什么所有的疾病实际上都局限于神经系统和 为什么在受影响部分的神经元中形成聚集物或包涵体 大脑。虽然提出了不同的解释，但我们之前的工作 支持以下解释：1)任何含有扩展序列的蛋白质 聚谷氨酰胺是转谷氨酰胺酶的一种异常活跃的底物。2) 作为冲动的一部分，神经元经历短暂的钙浓度升高 传导；这样的升高会激活神经元转谷氨酰胺酶。3) 谷氨酰胺转氨酶对含膨化聚谷氨酰胺的亨廷顿蛋白的作用 到其他蛋白质，并产生不溶于水的聚集体。不断形成的 共价交联的聚集体对神经元是致命的。 将通过研究1寻求进一步的证据来支持所有这些观点 )含膨化聚谷氨酰胺的包涵体的纯化 其他细胞成分及其对存在的分析( 谷氨酰基)赖氨酸交联物，2)受影响的蛋白质 大脑。尤其是微管蛋白，3)(约-谷氨酰基)赖氨酸的存在 亨廷顿病患者的脑和脊液受累部位 疾病。如果转谷氨酰胺酶的作用被确凿地证明， 可以设想转谷氨酰胺酶的形式来预防和治疗 抑制剂。

DESCRIPTION (adapted from applicant's abstract): Huntington disease and eight other central nervous system diseases are each caused by a protein containing an expanded sequence of polyglutamine. Each protein normally contains a polyglutamine sequence of not exceeding 40 residues but mutational expansion of this sequence in any of the proteins produces neuronal damage and a corresponding disease. If the cause can be precisely stated, the pathogenesis cannot. It must be explained why all the diseases are virtually confined to the nervous system and why aggregates or inclusions form in neurons of the affected parts of the brain. While different explanations have been proposed, our previous work supports the following explanation: 1) any protein bearing an expanded sequence of polyglutamine is an exceptionally active substrate of transglutaminase. 2) neurons undergo transient elevation in Ca++ concentration as part of impulse conduction; such a rise would activate the neuronal transglutaminase. 3) the action of transglutaminase couples huntingtin containing expanded polyglutamine to other proteins and produces insoluble aggregates. The constant formation of covalently cross-linked aggregates is lethal to neurons. Further evidence will be sought to support all of these points by studies of 1 ) the purification of inclusion bodies containing expanded polyglutamine from other cellular components and their analysis for the presence of ( abouty-glutamyl) lysine cross-links, 2) the proteins cross-linked in affected brain. especially tubulin, 3) the presence of ( about-glutamyl) lysine in affected parts of the brain and spinal fluid of patients with Huntington Disease. If the role of transglutaminase can be proven conclusively, a prophylaxis and a therapy can be envisioned in the form of transglutaminase inhibitors.