Tumor necrosis factor-like weak inducer of apoptosis and fibroblast growth factor-inducible 14 mediate cerebral ischemia-induced poly(ADP-ribose) polymerase-1 activation and neuronal death

• Type of Material: Article
• Authors: Woldeab B. Haile, Emory University; Ramiro Echeverry, Emory University; Fang Wu, Emory University; Johanna Guzman, Emory University; Jie An, Shandong University; Jialing Wu, Emory University; Manuel Yepes, Emory University
• Language: English
• Date: 2010-12-29
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010, Elsevier
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuroscience.2010.10.029
• Title of Journal or Parent Work: Neuroscience
• ISSN: 0306-4522
• Volume: 171
• Issue: 4
• Start Page: 1256
• End Page: 1264
• Grant/Funding Information: This work was supported in part by National Institutes of Health Grants NS-062073 and HL-095063 (to M.Y)
• Keywords: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK); Fibroblast growth factor-inducible 14 (Fn14); Poly(ADP-ribose) polymers (PAR); Poly(ADP-ribose)polymerase-1 (PARP-1); Cerebral ischemia
• Research Categories: Health Sciences, Pharmacology; Biology, Neuroscience

Abstract

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fibroblast growth factor-inducible 14 (Fn14) are expressed in neurons. Here we demonstrate that TWEAK induces a dose-dependent increase in neuronal death and that this effect is independent of TNF-α and mediated by NF-κB pathway activation. Incubation with TWEAK induces apoptotic cell death in wild-type (Wt) but not in Fn14 deficient (Fn14−/−) neurons. Intracerebral injection of TWEAK induces accumulation of poly(ADP-ribose) polymers (PAR) in Wt but not in Fn14−/− mice. Exposure to oxygen-glucose deprivation (OGD) conditions increases TWEAK and Fn14 mRNA expression in Wt neurons, and decreases cell survival in Wt but not in Fn14−/− or TWEAK deficient (TWEAK−/−) neurons. Experimental middle cerebral artery occlusion (MCAO) increases the expression of TWEAK and Fn14 mRNA and active caspase-3, and the cleavage of poly(ADP-ribose)polymerase-1 with accumulation of PAR in the ischemic area in Wt but not Fn14−/− mice. Together, these results suggest a model where in response to hypoxia/ischemia the interaction between TWEAK and Fn14 in neurons induces PARP-1 activation with accumulation of PAR polymers and cell death via NF-κB pathway activation. This is a novel pathway for hypoxia/ischemia-induced TWEAK-mediated cell death and a potential therapeutic target for ischemic stroke.