TRANSGLUTAMINASE AND DISEASES OF EXPANDED POLYGLUTAMINE

转谷氨酰胺酶和扩展聚谷氨酰胺疾病

• 批准号: 6197111
• 负责人: HOWARD GREEN
• 金额: $ 38.22万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-25 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6197111
• 关键词: Huntington's disease; cell line; crosslink; enzyme activity; genetically modified animals; glutamine; homopeptide; inclusion body; laboratory mouse; lysine; protein glutamine gamma glutamyltransferase; tubulin

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.

描述（改编自申请人的摘要）：亨廷顿病和八 其他中枢神经系统疾病都是由含有以下成分的蛋白质引起的： 多聚谷氨酰胺的扩展序列。每种蛋白质通常含有一个 多聚谷氨酰胺序列不超过40个残基，但突变扩展 任何蛋白质中的该序列都会产生神经元损伤和 相应的疾病。 如果可以明确病因，则不能明确发病机制。一定是 解释了为什么所有疾病实际上都局限于神经系统 为什么在受影响部分的神经元中形成聚集体或内含物 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）任何带有扩展序列的蛋白质 聚谷氨酰胺是转谷氨酰胺酶的异常活性底物。 2） 作为冲动的一部分，神经元的 Ca++ 浓度短暂升高 传导；这种升高会激活神经元转谷氨酰胺酶。 3） 转谷氨酰胺酶对含有扩展聚谷氨酰胺的亨廷顿蛋白的作用 与其他蛋白质结合并产生不溶性聚集体。不断形成 共价交联的聚集体对神经元是致命的。 将通过以下研究寻求进一步的证据来支持所有这些观点 1 ）纯化含有扩展的聚谷氨酰胺的包涵体 其他细胞成分及其存在的分析（ 约-谷氨酰）赖氨酸交联，2）受影响的蛋白质交联 脑。尤其是微管蛋白，3) 中存在（约谷氨酰）赖氨酸 亨廷顿病患者大脑和脊髓液受影响的部分 疾病。如果转谷氨酰胺酶的作用能够得到最终证明， 可以设想以转谷氨酰胺酶的形式进行预防和治疗 抑制剂。