Role of protein acetylation in Huntington's disease

描述(申请人提供)：亨廷顿病(HD)和其他扩张性聚谷氨酰胺疾病是由突变蛋白中谷氨酰胺重复序列的扩大引起的迟发性神经退行性疾病。目前，对于这些令人痛苦和致命的疾病，还没有治愈或有效的治疗方法。扩大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聚谷氨酰胺结构域(Htt)能结合并抑制几种乙酰基转移酶(如CBP、p300和P/CAF)的活性，并降低细胞培养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氏病的果蝇模型来测试神经病理可能是由于乙酰化和转录水平降低所致。我们发现，Le通过两种独立的机制抑制脱乙酰基过程。从遗传学或药理学角度(HDAC抑制剂)可降低致死率并阻止光感受器神经元的退化。这些结果强烈暗示了乙酰化在致病过程中的状态。由于包括SAHA在内的几种HDAC抑制剂目前已被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了潜在有用的药理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。在苍蝇和人类中，都存在组蛋白乙酰转移酶(HAT)和组蛋白脱乙酰基酶(HDAC)基因家族(约11个HAT和约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谷氨酰胺致病相关，并且我们将确定贡献是否是相加的。这些数据将提高我们对发病机制的遗传学和分子基础的理解，它们将确定治疗的新靶点，它们将揭示针对HAT/HDAC周期中的多种酶的联合治疗是否有效。

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.