Protein acetylation in Huntington's disease

亨廷顿病中的蛋白质乙酰化

• 批准号: 6562806
• 负责人: J LAWRENCE MARSH
• 金额: $ 35.1万
• 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/6562806
• 关键词: Drosophilidae; Huntington's disease; acetylation; acyltransferase; amidohydrolases; arthropod genetics; disease /disorder model; drug screening /evaluation; enzyme inhibitors; functional /structural genomics; gene interaction; gene mutation; genetic mapping; glutamine; homopeptide; molecular pathology; neural degeneration; nucleic acid repetitive sequence; posttranslational modifications; protein binding

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退行性疾病。目前，这些令人痛苦和致命的疾病尚无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标尚不清楚。我们发现亨廷顿蛋白 (Htt) 的多谷氨酰胺结构域结合并抑制多种乙酰转移酶（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。我们开发并使用了两种亨廷顿病果蝇模型来测试神经病理学可能由乙酰化和转录水平降低引起的可能性。我们发现通过两个独立的机制Le抑制脱乙酰化过程。通过遗传或药理学（HDAC 抑制剂）降低致死率并阻止感光神经元变性。这些结果强烈暗示了致病过程中乙酰化的状态。由于包括 SAHA 在内的多种 HDAC 抑制剂目前已获 FDA 批准用于其他临床环境或正处于 I 期临床试验中，因此 HDAC 抑制剂现在可以被认真考虑作为亨廷顿舞蹈病及相关疾病的潜在治疗药物。这是在果蝇疾病模型中发现潜在有用药物的早期案例之一。在这里，我们建议使用果蝇模型来扩展这些研究。果蝇和人体内都有 HAT（组蛋白乙酰转移酶）和 HDAC（组蛋白脱乙酰酶）基因家族（大约 11 个 HAT 和大约 9 个 HDAC 相关基因）。在这个项目中，我们将确定这些基因是否全部或仅部分与多聚谷氨酰胺发病机制相关，并且我们将确定贡献是否具有累加性。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，并将揭示针对 HAT/HDAC 循环中多种酶的联合疗法是否可能有效。