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

描述（由申请人提供）：对细胞的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（Glyceraldehyde 3-phosphate dehydrogenase， GAPDH）是细胞应激源修饰的分子之一，在细胞应激反应中起重要作用。由细胞应激源诱导的GAPDH的翻译后修饰允许其作为“传感器”和/或“中继”分子，通过与另一种称为7 in absentia homolog 1 （Siah）的蛋白形成复合物，将应激信号传递到细胞核中。在细胞核中，这种GAPDH-Siah复合物在细胞内引起各种变化，这些变化与细胞死亡和功能障碍有关。在帕金森病（PD）中发现的GAPDH- siah级联的激活，以及在亨廷顿病（HD）中发现的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，这一观点缺乏强有力的支持。我们最近的发现表明，称为凋亡信号调节激酶1 （ASK1）的第三种蛋白也可能能够触发GAPDH-Siah应激信号级联。通过拟议的培训资助，我们将提供证据证明ASK1激活GAPDH-Siah应激信号级联在亨廷顿病中；1)确定ASK1和GAPDH如何影响ASK1-Siah结合，2)阐明ASK1如何触发GAPDH-Siah应激信号，3)直接研究ASK1、GAPDH和Siah在HD病理中的作用。

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.