Spinocerebellar ataxia 7 protein function

脊髓小脑共济失调7蛋白功能

• 批准号: 7414356
• 负责人: PATRICK A GRANT
• 金额: $ 32.94万
• 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/7414356
• 关键词: Acetylation; Acetyltransferase; Address; Affect; Alleles; Ataxia; Biochemical; Biological Assay; Biological Models; CAG repeat; Cancer Etiology; Cell Line; Cell Nucleus; Cerebellum; Chromatin; Clinical; Code; Complement; Complex; Coupling; Defect; Deletion Mutation; Disease; Disease Progression; Disruption; Enzymes; Epitopes; Eukaryota; Eukaryotic Cell; Family; Functional disorder; Gene Expression Regulation; Genes; Goals; Grant; Growth; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Homologous Gene; Human; Huntington Disease; Immunoblotting; Investigation; Knockout Mice; Mammalian Cell; Mass Spectrum Analysis; Mediating; Modeling; Modification; Molecular; Mus; Mutant Strains Mice; Neurodegenerative Disorders; Neurons; Nuclear Hormone Receptors; Nucleosomes; Oncogene Proteins; Orthologous Gene; Pathogenesis; Pathology; Phenotype; Physiological; Play; Proteins; Purkinje Cells; RNA Polymerase II; Regulation; Research; Research Personnel; Research Project Grants; Retina; Retinal Defect; Role; SCA7 protein; Saccharomyces cerevisiae; Silver Staining; Testing; Therapeutic; Transcription Coactivator; Transcriptional Regulation; Trinucleotide Repeats; Tumor Suppressor Proteins; Type 7 Spinocerebellar Ataxia; Virus Diseases; Yeasts; base; cell type; chromatin immunoprecipitation; dosage; expression vector; histone acetyltransferase; human disease; immunoaffinity chromatography; inhibitor/antagonist; insight; leukemia; mouse model; mutant; nervous system disorder; polyglutamine; programs; promoter; protein function

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(申请人提供)：在真核细胞核中，DMA被组蛋白包装成核小体，核小体是染色质的重复亚单位。染色质基因表达的调控涉及组蛋白乙酰转移酶(HATS)等染色质修饰活性的作用。HAT酶经常与包含其他转录调节因子的大的多蛋白辅活化子复合体相关。这些观察结果为组蛋白乙酰化和转录调控的偶联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有关，并已在某些与白血病相关的易位中被描述，因此被认为在癌症的病因、病毒感染和核激素受体的作用中发挥核心作用。SAGA(SPT-Ada-Gcn5乙酰转移酶)和SLIK(SAGA-like)是两个同源的高度保守的多亚基HAT复合体，最初在酿酒酵母中发现。我们已经确定Sgf73/ySca7蛋白是人类蛋白ataxin-7的同源物，是SAGA和SLIK的组成部分。在其病理形式中，这种蛋白与神经退行性疾病脊髓小脑性共济失调7(SCA7)有关。酵母SCA7对于SAGA和SLIK的完整性和功能都是必需的，而人SCA7的聚谷氨酰胺扩展版本组装了一个特定缺乏核小体乙酰化的SAGA复合体。这些观察结果对人类SCA7蛋白在疾病发病机制中的功能具有重要意义。这项建议的目标是使用酵母、哺乳动物细胞系和小鼠作为模型，以阐明SCA7疾病病理背后的机制。其具体目的是确定SCA7蛋白的功能，检测聚谷氨酰胺扩张对组蛋白修饰和转录调控中SAGA家族功能的生化后果，并在小鼠模型中验证GCN5功能缺失在CMS和视网膜中参与SCA7病理的假说。通过确定这些蛋白质的生理作用，有可能深入了解编码具有聚谷氨酰胺束的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因SCA7扩增而导致的细胞功能障碍。这反过来可能为这种疾病和其他三核苷酸重复疾病(如亨廷顿病)提供可能的治疗方法。