A dual role for poly-ADP-ribosylation in spatial memory acquisition after traumatic brain injury in mice involving NAD+ depletion and ribosylation of 14-3-3gamma.
Poly(ADP-ribose) polymerase-1 (PARP-1) is a homeostatic enzyme that paradoxically contributes to disturbances in spatial memory acquisition after traumatic brain injury (TBI) in transgenic mice, thought to be related to depletion of its substrate nicotinamide adenine dinucleotide (NAD+). In this study, systemic administration of the PARP-1 inhibitor 5-iodo-6-amino-1,2-benzopyrone (INH2BP) after TBI preserved brain NAD+ levels and dose-dependently reduced poly-ADP-ribosylation 24 h after injury. While moderate-dose INH2BP improved spatial memory acquisition after TBI; strikingly, both injured- and sham-mice receiving high-dose INH2BP were unable to learn in the Morris-water maze. Poly-ADP-ribosylated peptides identified using a proteomics approach yielded several proteins potentially associated with memory, including structural proteins (tubulin alpha and beta, gamma-actin, and alpha-internexin neuronal intermediate filament protein) and 14-3-3gamma. Nuclear poly-ADP-ribosylation of 14-3-3gamma was completely inhibited by the dose of INH2BP that produced profound memory disturbances. Thus, partial inhibition of poly-ADP-ribosylation preserves NAD+ and improves functional outcome after TBI, whereas more complete inhibition impairs spatial memory acquisition independent of injury, and is associated with ribosylation of 14-3-3gamma.
Satchell
Margaret A
MA
Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Zhang
Xiaopeng
X
Kochanek
Patrick M
PM
Dixon
C Edward
CE
Jenkins
Larry W
LW
Melick
John
J
Szabó
Csaba
C
Clark
Robert S B
RS
D048948:14-3-3 Proteins; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism / Q000503:physiopathology*; D003374:Coumarins / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015180:Electrophoresis, Gel, Two-Dimensional; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009243:NAD / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000032:analysis / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D048948:14-3-3 Proteins; D003374:Coumarins; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011506:Proteins; D009243:NAD; C071383:5-iodo-6-amino-1,2-benzopyrone; D000246:Adenosine Diphosphate Ribose; D014446:Tyrosine 3-Monooxygenase; D011065:Poly(ADP-ribose) Polymerases