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

描述(申请人提供)：对细胞的压力可以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)是受细胞应激源修饰的分子之一，在细胞应激反应中发挥重要作用。由细胞应激源诱导的GAPDH的翻译后修饰使其能够发挥“传感器”和/或“继电器”分子的作用，通过与另一种名为SINVE in Abential Homolog 1(Siah)的蛋白质形成复合体，将应激信号传递到细胞核中。在细胞核中，这种GAPDH-Siah复合体导致细胞内的各种变化，这些变化与细胞死亡和功能障碍有关。在帕金森病(PD)中GAPDH-Siah级联的激活，以及在亨廷顿病(HD)中GAPDH和Huntingtin的核共存，表明GAPDH-Siah级联可能推动这些神经退行性疾病的发生。然而，这一想法缺乏强有力的支持。我们最近的发现表明，第三种名为凋亡信号调节蛋白1(ASK1)的蛋白可能也能够触发GAPDH-Siah应激信号级联反应。通过拟议的培训拨款，我们将提供证据证明ASK1通过以下方式激活亨廷顿病中的GAPDH-Siah应激信号级联：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)直接检测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.