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.

• 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)
• 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

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