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

Johns Hopkins University, Baltimore MD

Investigators

Linked publications & trials

Abstract

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.