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

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。 公共卫生相关性：这种新的应激信号级联反应的特征将有助于我们了解神经退行性疾病（如HD）进展的分子机制。在神经退行性疾病的背景下，这种级联反应的特征可能有助于我们确定治疗这些疾病的潜在治疗靶点。

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. PUBLIC HEALTH RELEVANCE: Characterization of this novel stress-signaling cascade will help us understand the molecular mechanism underpining the progression of neurodegenerative diseases, such as HD. Characterization of this cascade in the context of neurodegeneration may help us identify potential therapeutic targets for the treatment of these diseases.