Spinocerebellar ataxia 7 protein function

脊髓小脑共济失调7蛋白功能

• 批准号: 7105990
• 负责人: PATRICK A GRANT
• 金额: $ 34.72万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105990
• 关键词: Saccharomyces; acyltransferase; cell line; cerebellar ataxia /dyskinesia; chromatin immunoprecipitation; enzyme inhibitors; gene expression; genetic transcription; genetically modified animals; immunoprecipitation; laboratory mouse; mass spectrometry; nervous system disorder; northern blottings; polyglutamates; polymerase chain reaction; protein structure function; western blottings

DESCRIPTION (provided by applicant): In the eukaryotic cell nucleus, DMA is packaged by histones into nucleosomes, the repeating subunits of chromatin. The regulation of gene expression from chromatin involves the action of chromatin modifying activities including histone acetlytransferases (HATs). HAT enzymes are frequently associated with large multiprotein coactivator complexes that contain other transcriptional regulators. These observations have provided a direct molecular basis for the coupling of histone acetylation and the regulation of transcription. HAT proteins are known to associate with cellular oncoproteins and tumor suppressor proteins and have been described in certain translocations associated with leukemias and thus have been postulated to play a central role in the etiology cancer as well as viral infection and nuclear hormone receptor action. SAGA (Spt- Ada-Gcn5 Acetyltransferase) and SLIK (SAGA-Like) are 2 homologous and highly conserved multi-subunit HAT complexes that were originally identified in Saccharomyces cerevisiae. We have identified the protein Sgf73/ySca7, a homologue of the human protein ataxin-7, as a component of SAGA and SLIK. In its pathological form, this protein is responsible for the neurodegenerative disease spinocerebellar ataxia 7 (SCA7). Yeast Sca7 is necessary for the integrity and function of both SAGA and SLIK and a polyglutamine expanded version of human Sca7 assembles a SAGA complex that is specifically deficient in nucleosome acetylation. These observations have significant implications for the function of the human Sca7 protein in disease pathogenesis. The goals of this proposal are to use yeast, mammalian cell lines and mice as models to elucidate the mechanism behind the pathology of the SCA7 disorder. The Specific Aims are to determine the function of Sca7 protein, to examine the biochemical consequences of polyglutamine expansion on function of the SAGA family of complexes in histone modification and transcriptional regulation and test the hypothesis that depletion of GCN5 function in the CMS and retina contributes to SCA7 pathology in a mouse model. By identifying the physiological roles of these proteins it may be possible to gain insight as to how pathological alleles coding for proteins with polyglutamine tracts promote disease progression. Furthermore we aim to investigate the use of histone deacetylase inhibitors for the treatement of cellular dysfunction as a consequence SCA7 expansion. This, in turn, may suggest possible therapeutic treatments for this and other trinucleotide repeat diseases, such as Huntington's disease.

描述（由申请人提供）：在真核细胞核中，DMA 由组蛋白包装到核小体（染色质的重复亚基）中。染色质基因表达的调节涉及染色质修饰活性的作用，包括组蛋白乙酰转移酶 (HAT)。 HAT 酶经常与含有其他转录调节因子的大型多蛋白共激活剂复合物相关。这些观察结果为组蛋白乙酰化的偶联和转录调控提供了直接的分子基础。已知 HAT 蛋白与细胞癌蛋白和肿瘤抑制蛋白相关，并且已在与白血病相关的某些易位中被描述，因此被认为在病因学癌症以及病毒感染和核激素受体作用中发挥核心作用。 SAGA (Spt-Ada-Gcn5 乙酰转移酶) 和 SLIK (SAGA-Like) 是 2 个同源且高度保守的多亚基 HAT 复合物，最初在酿酒酵母中发现。我们已经鉴定出蛋白质 Sgf73/ySca7（人类蛋白质 ataxin-7 的同源物）是 SAGA 和 SLIK 的组成部分。在其病理形式中，该蛋白与神经退行性疾病脊髓小脑共济失调 7 (SCA7) 相关。酵母 Sca7 对于 SAGA 和 SLIK 的完整性和功能是必需的，并且人类 Sca7 的聚谷氨酰胺扩展版本组装了一个在核小体乙酰化方面特别缺乏的 SAGA 复合物。这些观察结果对于人类 Sca7 蛋白在疾病发病机制中的功能具有重要意义。该提案的目标是使用酵母、哺乳动物细胞系和小鼠作为模型来阐明 SCA7 疾病的病理机制。具体目标是确定 Sca7 蛋白的功能，检查多聚谷氨酰胺扩增对组蛋白修饰和转录调控中 SAGA 复合物家族功能的生化影响，并测试 CMS 和视网膜中 GCN5 功能的缺失导致小鼠模型中 SCA7 病理学的假设。通过识别这些蛋白质的生理作用，有可能深入了解编码多聚谷氨酰胺束蛋白质的病理等位基因如何促进疾病进展。此外，我们的目标是研究组蛋白脱乙酰酶抑制剂用于治疗 SCA7 扩增导致的细胞功能障碍的用途。反过来，这可能为这种疾病和其他三核苷酸重复疾病（例如亨廷顿病）提供可能的治疗方法。