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

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
  • 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

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: