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: 6394110
• 负责人: HOWARD GREEN
• 金额: $ 40.39万
• 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/6394110
• 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（改编自申请人摘要）：亨廷顿病和8