Role of protein acetylation in Huntington's disease

蛋白质乙酰化在亨廷顿病中的作用

• 批准号: 6685258
• 负责人: J LAWRENCE MARSH
• 金额: $ 35.66万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6685258
• 关键词: Role; protein; acetylation; Huntington; disease

DESCRIPTION (provided by applicant): Huntington's disease (HD) and other expanded polyglutamine diseases are late onset neurodegenerative diseases caused by expansion of a glutamine repeat in the mutant protein. Currently, no cure or effective treatment for these agonizing and lethal diseases exists. The pathogenic target of the expanded glutamine repeat is unknown. We find that the polyglutamine domain of Huntingtin (Htt) binds to and inhibits the activity of several acetyltransferases (e.g.CBP, p300, and P/CAF) and reduces the level of acetylated histones in cell culture. We have developed and used two Drosophila models of Huntington's disease to test the possibility that neuropathology may result from reduced levels of acetylation and transcription. We find that inhibition of the deacetylation process by two independent mechanisms Le. genetically or pharmacologically (HDAC inhibitors) reduces lethality and arrests photoreceptor neuron degeneration. These results strongly implicate the state of acetylation in the pathogenic process. As several HDAC inhibitors, including SAHA, are currently FDA approved for use in other clinical settings or are in Phase I clinical trials, HDAC inhibitors can now be seriously considered as potential therapeutic agents for Huntington's disease and related diseases. This represents one of the early cases where potentially useful pharmacologic agents have been identified in a Drosophila model of disease. Here we propose to extend these studies using the Drosophila model. In both flies and man there are families of HAT (Histone Acetyl Transferase) and HDAC (Histone DeACetylase) genes (approximately 11 HATs and approximately 9 HDAC related genes). In this project, we will determine whether all or just some of these genes are relevant to polyglutamine pathogenesis and we will determine whether contributions are additive. These data will improve our understanding of the genetic and molecular basis of pathogenesis, they will identify new targets for therapeutics and they will reveal whether combination therapies targeted at multiple enzymes in the HAT/HDAC cycle might be effective.

描述（由申请人提供）：亨廷顿氏病（HD）和其他扩展的多聚谷氨酰胺疾病是由突变蛋白中谷氨酰胺重复序列的扩展引起的迟发性神经变性疾病。目前，对这些痛苦和致命的疾病没有治愈或有效的治疗方法。扩展的谷氨酰胺重复序列的致病靶点尚不清楚。我们发现亨廷顿蛋白的多聚谷氨酰胺结构域（Htt）结合并抑制几种乙酰转移酶（例如CBP、p300和P/CAF）的活性，并降低细胞培养物中乙酰化组蛋白的水平。我们已经开发并使用了两种亨廷顿病的果蝇模型来测试乙酰化和转录水平降低导致神经病理学的可能性。我们发现，通过两个独立的机制Le。基因或HDAC抑制剂可降低致死率并阻止感光神经元变性。这些结果强烈暗示了乙酰化状态的致病过程。由于包括SAHA在内的几种HDAC抑制剂目前被FDA批准用于其他临床环境或处于I期临床试验中，HDAC抑制剂现在可以被认真考虑作为亨廷顿病和相关疾病的潜在治疗剂。这代表了在果蝇疾病模型中发现潜在有用药剂的早期案例之一。在这里，我们建议使用果蝇模型来扩展这些研究。在果蝇和人类中，存在HAT（组蛋白乙酰转移酶）和HDAC（组蛋白去乙酰化酶）基因的家族（大约11个HAT和大约9个HDAC相关基因）。在这个项目中，我们将确定是否所有或只是一些这些基因与多聚谷氨酰胺的发病机制，我们将确定是否贡献是加性的。这些数据将提高我们对发病机制的遗传和分子基础的理解，它们将确定新的治疗靶点，它们将揭示针对HAT/HDAC循环中多种酶的联合治疗是否有效。