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

doi:10.1038/nm.2387

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

Division of Biotechnology

Research output: Contribution to journal › Article › peer-review

183 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 language	English
Pages (from-to)	692-699
Number of pages	8
Journal	Nature Medicine
Volume	17
Issue number	6
DOIs	https://doi.org/10.1038/nm.2387
State	Published - Jun 2011

Bibliographical note

Funding Information:
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.

Access to Document

10.1038/nm.2387

Cite this

@article{4aa11ae3668146e4a9252c55539c85c3,

title = "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.",

author = "Andrabi, {Shaida A.} and Kang, {Ho Chul} and Haince, {Jean Fran{\c c}ois} and Lee, {Yun Il} and Jian Zhang and Zhikai Chi and West, {Andrew B.} and Koehler, {Raymond C.} and Poirier, {Guy G.} and Dawson, {Ted M.} and Dawson, {Valina L.}",

note = "Funding Information: 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.",

year = "2011",

month = jun,

doi = "10.1038/nm.2387",

language = "English",

volume = "17",

pages = "692--699",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "6",

}

TY - JOUR

T1 - Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death

AU - Andrabi, Shaida A.

AU - Kang, Ho Chul

AU - Haince, Jean François

AU - Lee, Yun Il

AU - Zhang, Jian

AU - Chi, Zhikai

AU - West, Andrew B.

AU - Koehler, Raymond C.

AU - Poirier, Guy G.

AU - Dawson, Ted M.

AU - Dawson, Valina L.

N1 - Funding Information: 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.

PY - 2011/6

Y1 - 2011/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79958079994&partnerID=8YFLogxK

U2 - 10.1038/nm.2387

DO - 10.1038/nm.2387

M3 - Article

C2 - 21602803

AN - SCOPUS:79958079994

SN - 1078-8956

VL - 17

SP - 692

EP - 699

JO - Nature Medicine

JF - Nature Medicine

IS - 6

ER -

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

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this