Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death
Open accessAbstract
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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ADPRHL2 and RNF146 prevent AIF release and consequent RCD by decreasing poly(ADP-ribose) levels and availability.
“the poly(ADP-ribose)-degrading protein ADP-ribosylhydrolase like 2 (ADPRHL2; also known as ARH3) and the poly(ADP-ribose)-binding protein ring finger protein 146 (RNF146; best known as IDUNA) prevent AIF release and consequent RCD as they decrease poly(ADP-ribose) levels and availability, respectively [662, 668].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [662]
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- Authors
- 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.
- Affiliations
- Johns Hopkins University (US)
- Centre hospitalier universitaire de Québec (CA)
- Corresponding author
- Dawson, Ted M
- Dawson, Valina L
- ORCID
- Venue
- Nature Medicine
- Published
- 2011-05-22
- Volume
- 17
- Issue
- 6
- Pages
- 692-699
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC3709257
- OpenAlex
- W1995005155
- Cited by
- 216
- References
- 46
- Citations by year
- 2026: 8 · 2025: 3 · 2024: 19 · 2023: 14 · 2022: 12 · 2021: 17 · 2020: 12 · 2019: 16 · 2018: 19 · 2017: 18 · 2016: 12 · 2015: 20 · 2014: 13 · 2013: 16 · 2012: 12
- FWCI
- 5.85
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Canadian Institutes of Health Research
- National Institute on Drug Abuse (P50DA000266, DA000266)
- National Institute of Neurological Disorders and Stroke (R01NS051764, NS067525, NS039148, NS051764, R01NS067525, P01NS039148)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- PARP1, parthanatos, glutamate excitotoxicity, NMDA receptor, stroke, neuroprotection, neuronal cell death, middle cerebral artery occlusion
- MeSH terms
- Poly (ADP-Ribose) Polymerase-1, Animals, Brain, Calcium, Mitochondria, Nerve Tissue Proteins, Poly Adenosine Diphosphate Ribose, Poly(ADP-ribose) Polymerases, Protein Binding, Blotting, Northern, Receptors, N-Methyl-D-Aspartate, Cell Death, Glutamic Acid, Stroke, Apoptosis Inducing Factor, Mice
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