Characterization of Poly(ADP-ribose) (PAR) as a death signal in PARP-1 dependent cell death
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Date
2015-05-08
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Johns Hopkins University
Abstract
Poly(ADP-ribose)polymerase (PARP) overactivation induces cell death called parthanatos via production of large swells of PAR. Parthanatos is apparent in debilitating diseases such as stroke and Parkinson’s disease. PAR is complex polymer of ADP-ribose with different sizes and branching structures. Complex PAR is more toxic as compared to shorter length PAR. The role of different PAR species play in disease complexity and progression is still unknown. Moreover, the tools currently available are not sensitive enough to detect the differences in PAR species. While the current antibodies available are capable of detecting PAR for immunoblot analysis and immunohistochemistry analysis, the detection threshold is high and specificity for varying PAR structures is low. Here, we generated a panel of recombinant antibodies using phage display HuCal technology to effectively detect PAR species in different disease models. PAR induces cell death via translocation of AIF to the nucleus. To further understand how different species of PAR regulate the nuclear translocation of AIF, we generated a PAR-binding mutant AIF transgenic knock-in mouse. Induction of stroke via middle cerebral artery occlusion (MCAO) is used to detect the PAR-induced cell death.
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Keywords
PARP1, Parkinson's Disease, Stroke, Neurotoxicity, PAR