Role of ASK1 for GAPDH-Siah binding and GAPDH-Siah stress-signaling in HD

ASK1 在 HD 中 GAPDH-Siah 结合和 GAPDH-Siah 应激信号传导中的作用

• 批准号: 8394927
• 负责人: Carlos Alberto Tristan
• 金额: $ 4.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-27 至 2013-12-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394927
• 关键词: Address; Affect; Apoptosis; Binding; Binding Proteins; Cell Death; Cell Nucleus; Cells; Cellular Stress Response; Cessation of life; Complex; Consensus; Consensus Sequence; Cysteine; Data; Disease; Disease Progression; Enzyme Gene; Exposure to; Fibroblasts; Functional disorder; Genetic Transcription; Glyceraldehyde-3-Phosphate Dehydrogenases; Grant; Histones; Homologous Gene; Huntington Disease; In Vitro; Ischemia; Knockout Mice; Laboratories; MAP3K5 gene; Mediating; Mentors; Modeling; Molecular; Monitor; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Nuclear Localization Signal; Nuclear Translocation; Oxidative Stress; Parkinson Disease; Pathology; Phosphorylation; Phosphorylation Site; Play; Post-Translational Protein Processing; Proteins; RNA Interference; Recombinant Proteins; Recombinants; Reporting; Role; Signal Pathway; Signal Transduction; Site; Staging; Stress; Training; base; cytotoxicity; human Huntingtin protein; in vitro Assay; in vitro testing; mouse model; mutant; novel; oxidation; polyglutamine; protein complex; public health relevance; research study; response; sensor; stressor; therapeutic target

DESCRIPTION (provided by applicant): Stress to cells can directly influence the expression, functional role, and the subcellular distribution of molecules within cells leading to cell death and/or dysfunction. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is one of these molecules modified by cell stressors and plays a critical role in cellular stress response. Posttranslational modifications of GAPDH induced by cell stressors allow it to function as a "sensor" and/or "relay" molecule that conveys stress signals into the nucleus by forming a complex with another protein called seven in absentia homolog 1 (Siah). In the nucleus this GAPDH-Siah complex causes various changes within the cell that have been associated with cell death and dysfunction. Activation of the GAPDH-Siah cascade demonstrated in Parkinson's disease (PD), and the nuclear colocalization of GAPDH and Huntingtin seen in Huntington's disease (HD), suggest that the GAPDH-Siah cascade may drive these neurodegenerative diseases. However, strong support for this idea is lacking. Our recent finds suggests that a third protein called apoptosis signal regulating kinase 1 (ASK1) might also be capable of triggering the GAPDH-Siah stress signaling cascade. Through the proposed training grant we will provide evidence to demonstrate that ASK1 activates the GAPDH-Siah stress signaling cascade in Huntington's disease by; 1) determining how ASK1 and GAPDH affect ASK1-Siah binding, 2) clarifying how ASK1 triggers GAPDH-Siah stress signaling and 3) directly examining the role of ASK1, GAPDH, and Siah in HD pathology.

描述（由申请人提供）：细胞应激可直接影响细胞内分子的表达、功能作用和亚细胞分布，导致细胞死亡和/或功能障碍。甘油醛3-磷酸脱氢酶（GAPDH）是一种被细胞应激物修饰的分子，在细胞应激反应中起着关键作用。由细胞应激物诱导的GAPDH的翻译后修饰允许其作为“传感器”和/或“中继”分子起作用，其通过与另一种称为七缺席同源物1（Siah）的蛋白质形成复合物将应激信号传递到细胞核中。在细胞核中，这种GAPDH-Siah复合物会引起细胞内的各种变化，这些变化与细胞死亡和功能障碍有关。在帕金森病（PD）中证实的GAPDH-Siah级联的激活，以及在亨廷顿病（HD）中看到的GAPDH和亨廷顿蛋白的核共定位，表明GAPDH-Siah级联可能驱动这些神经退行性疾病。然而，这一想法缺乏强有力的支持。我们最近的发现表明，称为凋亡信号调节激酶1（ASK 1）的第三种蛋白质也可能能够触发GAPDH-Siah应激信号级联反应。通过拟议的培训补助金，我们将提供证据，证明ASK 1激活亨廷顿病中的GAPDH-Siah应激信号级联; 1）确定ASK 1和GAPDH如何影响ASK 1-Siah结合，2）阐明ASK 1如何触发GAPDH-Siah应激信号，3）直接检查ASK 1，GAPDH和Siah在HD病理学中的作用。