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.Background: The link between poly(ADP-ribose) polymerase-1 (PARP-1) and nuclear-translocated glyceradehyde-3-phosphate dehydrogenase (GAPDH) in neurons under oxidative/nitrosative stress remains unknown.Results: The N terminus of nuclear GAPDH binds with PARP-1, and this complex promotes PARP-1 overactivation both in vitro and in vivo.Conclusion: Nuclear GAPDH is a key PARP-1 regulator.Significance: GAPDH/PARP-1 signaling underlies oxidative/nitrosative stress-induced brain damage such as 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. Background: The link between poly(ADP-ribose) polymerase-1 (PARP-1) and nuclear-translocated glyceradehyde-3-phosphate dehydrogenase (GAPDH) in neurons under oxidative/nitrosative stress remains unknown. Results: The N terminus of nuclear GAPDH binds with PARP-1, and this complex promotes PARP-1 overactivation both in vitro and in vivo. Conclusion: Nuclear GAPDH is a key PARP-1 regulator. Significance: GAPDH/PARP-1 signaling underlies oxidative/nitrosative stress-induced brain damage such as stroke.