TRANSGLUTAMINASE AND DISEASES OF EXPANDED POLYGLUTAMINE

描述（改编自申请人的摘要）：亨廷顿病和八种 其他中枢神经系统疾病都是由一种蛋白引起的， 多聚谷氨酰胺的扩展序列。每种蛋白质通常含有 多聚谷氨酰胺序列不超过40个残基，但突变扩增 任何一种蛋白质中的这种序列都会引起神经元损伤， 相应的疾病。 如果病因可以精确说明，那么发病机制就不能。必须 解释了为什么所有的疾病实际上都局限于神经系统， 为什么聚集体或内含物形成在神经元的受影响的部分， 个脑袋虽然已经提出了不同的解释，但我们以前的工作 支持以下解释：1）任何带有扩展序列的蛋白质 多聚谷氨酰胺是一种非常活跃的转氨酶底物。（二） 作为冲动的一部分，神经元经历Ca++浓度的短暂升高 传导;这种升高会激活神经元转氨酶。3)的 谷氨酰胺转氨酶偶联亨廷顿蛋白的作用 与其他蛋白质结合并产生不溶性聚集体。不断形成的 共价交联的聚集体对神经元是致命的。 进一步的证据将寻求支持所有这些点的研究1 ）含有扩增的多聚谷氨酰胺的包涵体的纯化 其他细胞成分及其分析的存在（ 2）受影响的蛋白质交联， 个脑袋特别是微管蛋白，3）在微管蛋白中存在（β-谷氨酰）赖氨酸， 亨廷顿舞蹈症患者的脑部和脊髓液受影响部位 疾病如果转氨酶的作用可以得到结论性的证明， 预防和治疗可以设想为转氨酶的形式 抑制剂的

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.