Poly(ADP-ribose) (PAR) polymer is a death signal.
Excessive activation of the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP-1) plays a prominent role in various of models of cellular injury. Here, we identify poly(ADP-ribose) (PAR) polymer, a product of PARP-1 activity, as a previously uncharacterized cell death signal. PAR polymer is directly toxic to neurons, and degradation of PAR polymer by poly(ADP-ribose) glycohydrolase (PARG) or phosphodiesterase 1 prevents PAR polymer-induced cell death. PARP-1-dependent, NMDA excitotoxicity of cortical neurons is reduced by neutralizing antibodies to PAR and by overexpression of PARG. Neuronal cultures with reduced levels of PARG are more sensitive to NMDA excitotoxicity than WT cultures. Transgenic mice overexpressing PARG have significantly reduced infarct volumes after focal ischemia. Conversely, mice with reduced levels of PARG have significantly increased infarct volumes after focal ischemia compared with WT littermate controls. These results reveal PAR polymer as a signaling molecule that induces cell death and suggests that interference with PAR polymer signaling may offer innovative therapeutic approaches for the treatment of cellular injury.
Andrabi
Shaida A
SA
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Kim
No Soo
NS
Yu
Seong-Woon
SW
Wang
Hongmin
H
Koh
David W
DW
Sasaki
Masayuki
M
Klaus
Judith A
JA
Otsuka
Takashi
T
Zhang
Zhizheng
Z
Koehler
Raymond C
RC
Hurn
Patricia D
PD
Poirier
Guy G
GG
Dawson
Valina L
VL
Dawson
Ted M
TM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D051379:Mice; D008970:Molecular Weight; D009474:Neurons / Q000187:drug effects; D011064:Poly Adenosine Diphosphate Ribose / Q000737:chemistry / Q000633:toxicity*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011108:Polymers / Q000737:chemistry / Q000633:toxicity*; D015398:Signal Transduction
D011108:Polymers; D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases