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 mediates brain damage when it is over-activated by oxidative/nitrosative stress. Nonetheless, it remains unclear how is activated in neuropathological contexts. Here we report that Pduanyu37-1 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 Wild-type (WT) but not mutant GAPDH, that lacks the ability to bind can promote Pduanyu37-1 activation. Importantly, disrupting this interaction significantly diminishes Pduanyu37-1 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 Pduanyu37-1 activity, and its signaling underlies the pathology of oxidative/nitrosative stress-induced brain damage including stroke.

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