June 12, 2017

Dr. Hasem Habelhah received a two-year NIH R21 grant entitled, ‘HtrA2-mediated RIP1 Cleavage Regulates Neuronal Inflammation and Death’. The goals of this project are to define the molecular mechanisms by which HtrA2-mediated cleavage of RIP1 regulates inflammation and cell death in striatal neurons in response to TNF-alpha and oxidative stress. RIP1 is a dual-function protein that plays key roles in cell survival, apoptosis and necroptosis in response to TNF-alpha and oxidative stress. HtrA2 is a serine protease that also regulates cell survival under conditions of oxidative stress. HtrA2 knockout (KO) mice exhibit a neurodegenerative disorder characteristic of Parkinson’s disease (PD). Mutations in the human HTRA2 gene have also been found in sporadic PD patients. However, the substrate(s) responsible for the PD-like phenotype in HrtA2 KO mice have not yet been identified. By unbiased in vitro binding and cleavage assays, we identified RIP1 as a substrate of HtrA2 that regulates inflammation and apoptosis in HtrA2 KO cells. This proposal will assess the pathological relevance of the RIP1-dependent pathways in the onset and progression of basal ganglia disorder in HtrA2-mutant mice. Thus, the positive outcomes from this project have the potential to guide the development of novel biomarkers and therapeutic approaches for PD patients.