Abstract |
In addition to its role in DNA repair, nuclear poly(ADP-ribose) polymerase-1 (PARP-1) mediates brain damage when it is over-activated by oxidative/nitrosative stress. Nonetheless, it remains unclear how PARP-1 is activated in neuropathological contexts. Here we report that PARP-1 interacts with a pool of glyceradehyde-3-phosphate dehydrogenase (GAPDH) that translocates into the nucleus under oxidative/nitrosative stress both in vitro and in vivo. A well conserved amino acid at the N terminus of GAPDH determines its protein binding with PARP-1. Wild-type (WT) but not mutant GAPDH, that lacks the ability to bind PARP-1, can promote PARP-1 activation. Importantly, disrupting this interaction significantly diminishes PARP-1 overactivation and protects against both brain damage and neurological deficits induced by middle cerebral artery occlusion/reperfusion in a rat stroke model. Together, these findings suggest that nuclear GAPDH is a key regulator of PARP-1 activity, and its signaling underlies the pathology of oxidative/nitrosative stress-induced brain damage including stroke.
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Authors | Hidemitsu Nakajima, Takeya Kubo, Hideshi Ihara, Takatoshi Hikida, Teruko Danjo, Masatoshi Nakatsuji, Neelam Shahani, Masanori Itakura, Yoko Ono, Yasu-Taka Azuma, Takashi Inui, Atsushi Kamiya, Akira Sawa, Tadayoshi Takeuchi |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 290
Issue 23
Pg. 14493-503
(Jun 05 2015)
ISSN: 1083-351X [Electronic] United States |
PMID | 25882840
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. |
Chemical References |
- Nitro Compounds
- Glyceraldehyde-3-Phosphate Dehydrogenases
- Parp1 protein, rat
- Poly (ADP-Ribose) Polymerase-1
- Poly(ADP-ribose) Polymerases
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Topics |
- Amino Acid Sequence
- Animals
- Brain
(blood supply, enzymology, metabolism, pathology)
- Cell Line
- Cell Nucleus
(enzymology, metabolism, pathology)
- Enzyme Activation
- Glyceraldehyde-3-Phosphate Dehydrogenases
(analysis, metabolism)
- Humans
- Infarction, Middle Cerebral Artery
(enzymology, metabolism, pathology)
- Male
- Models, Molecular
- Molecular Sequence Data
- Nitro Compounds
(analysis, metabolism)
- Oxidative Stress
- Poly (ADP-Ribose) Polymerase-1
- Poly(ADP-ribose) Polymerases
(analysis, metabolism)
- Rats
- Rats, Wistar
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