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

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.

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Figure 1: Iduna is an NMDA-induced neuroprotective protein.
Figure 2: Iduna is neuroprotective.
Figure 3: PAR binding activity of Iduna.
Figure 4: PAR-binding property of Iduna mediates neuroprotection.
Figure 5: Iduna does not interfere with NMDA-induced changes in Ca2+ or mitochondrial Ca2+ loading but prevents AIF translocation and reductions in Δψm.
Figure 6: Iduna is neuroprotective in vivo.

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Acknowledgements

pROSA26PA was provided by P. Soriano (University of Washington). This work was supported by grants from the US National Institutes of Health National Institute of Neurological Disorders and Stroke (NS039148, NS067525 and NS051764) and National Institute on Drug Abuse (DA000266) and the McKnight Endowment for the Neurosciences. S.A.A. is an American Heart Research Postdoctoral Fellow. G.G.P. was supported from a Canadian Institutes Health Research grant and holds a Research Chair in Proteomics. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases.

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Contributions

S.A.A. and H.C.K. designed and performed in vitro and in vivo experiments. Y.-I.L. performed the RT-PCR and some western blots for Figure 1. J.Z. and R.C.K. conducted and analyzed the middle cerebral artery occlusion experiments. Z.C. and A.B.W. initially purified Iduna lentiviral particles and performed some cell death assays. Z.C. supplied OGD samples for Figure 1g. J.-F.H. and G.G.P. purified PAR-specific antibodies and conducted in vitro PAR activity assays. T.M.D. and V.L.D. formulated the hypothesis, initiated and organized the study and wrote the manuscript. S.A.A., H.C.K., R.C.K., G.G.P., T.M.D. and V.L.D. contributed to the final manuscript.

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Correspondence to Ted M Dawson or Valina L Dawson.

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Andrabi, S., Kang, H., Haince, JF. et al. Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death. Nat Med 17, 692–699 (2011). https://doi.org/10.1038/nm.2387

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