Journal
NATURE MEDICINE
Volume 17, Issue 6, Pages 692-U82Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2387
Keywords
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Funding
- US National Institutes of Health National Institute of Neurological Disorders and Stroke [NS039148, NS067525, NS051764]
- National Institute on Drug Abuse [DA000266]
- McKnight Endowment for the Neurosciences
- Canadian Institutes Health Research
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Glutamate acting on N-methyl-D-aspartate (NMDA) receptors induces neuronal injury following stroke, through activation of poly(ADPribose) 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.
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