Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death

Shaida A. Andrabi, Ho Chul Kang, Jean François Haince, Yun Il Lee, Jian Zhang, Zhikai Chi, Andrew B. West, Raymond C. Koehler, Guy G. Poirier, Ted M. Dawson, Valina L. Dawson

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127 Scopus citations

Abstract

Glutamate acting on N-methyl-D-aspartate (NMDA) receptors induces neuronal injury following stroke, through activation of poly(ADP-ribose) polymerase-1 (PARP-1) and generation of the death molecule poly(ADP-ribose) (PAR) polymer. Here we identify Iduna, a previously undescribed NMDA receptor-"induced survival protein that is neuroprotective against glutamate NMDA receptor-"mediated excitotoxicity both in vitro and in vivo and against stroke through interfering with PAR polymer-"induced cell death (parthanatos). Iduna's protective effects are independent and downstream of PARP-1 activity. Iduna is a PAR polymer-"binding protein, and mutation at the PAR polymer binding site abolishes the PAR binding activity of Iduna and attenuates its protective actions. Iduna is protective in vivo against NMDA-induced excitotoxicity and middle cerebral artery occlusion-"induced stroke in mice. To our knowledge, these results define Iduna as the first known endogenous inhibitor of parthanatos. Interfering with PAR polymer signaling could be a new therapeutic strategy for the treatment of neurologic disorders.

Original languageEnglish (US)
Pages (from-to)692-699
Number of pages8
JournalNature medicine
Volume17
Issue number6
DOIs
StatePublished - Jun 1 2011

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Andrabi, S. A., Kang, H. C., Haince, J. F., Lee, Y. I., Zhang, J., Chi, Z., West, A. B., Koehler, R. C., Poirier, G. G., Dawson, T. M., & Dawson, V. L. (2011). Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death. Nature medicine, 17(6), 692-699. https://doi.org/10.1038/nm.2387