title: 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.affiliation: From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka 5988531, Japan, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka 5988531, Japan.
authors.forename: Takeya
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Department of Science, Osaka Prefecture University, Osaka 5988531, Japan.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ihara
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 6068501, Japan, PRESTO, Japan Science and Technology Agency, Saitama 3320012, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Hikida
authors.affiliation: Department of Systems Biology, Osaka Bioscience Institute, Osaka 5650874, Japan.
authors.forename: Teruko
authors.initials: T
authors.lastname: Danjo
authors.affiliation: Laboratory of Biological Macromolecules, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka 5998531, Japan, and.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nakatsuji
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors.forename: Neelam
authors.initials: N
authors.lastname: Shahani
authors.affiliation: From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka 5988531, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Itakura
authors.affiliation: From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka 5988531, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ono
authors.affiliation: From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka 5988531, Japan.
authors.forename: Yasu-Taka
authors.initials: YT
authors.lastname: Azuma
authors.affiliation: Laboratory of Biological Macromolecules, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka 5998531, Japan, and.
authors.forename: Takashi
authors.initials: T
authors.lastname: Inui
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kamiya
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
authors.affiliation: From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka 5988531, Japan, takeuchi@vet.osakafu-u.ac.jp.
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Takeuchi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009574:Nitro Compounds / Q000032:analysis / Q000378:metabolism; D018384:Oxidative Stress; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D009574:Nitro Compounds; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: ischemia; nitric oxide; oxidative stress; signaling; stroke