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Nuclear-translocated Glyceraldehyde-3-phosphate Dehydrogenase Promotes Poly(ADP-ribose) Polymerase-1 Activation during Oxidative/Nitrosative Stress in Stroke.

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.
AuthorsHidemitsu 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
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 23 Pg. 14493-503 (Jun 5 2015) ISSN: 1083-351X [Electronic] United States
PMID25882840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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) Polymerases
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) Polymerases (analysis, metabolism)
  • Rats
  • Rats, Wistar

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