Andrabi Shaida A, Kim No Soo, Yu Seong-Woon, Wang Hongmin, Koh David W, Sasaki Masayuki, Klaus Judith A, Otsuka Takashi, Zhang Zhizheng, Koehler Raymond C, Hurn Patricia D, Poirier Guy G, Dawson Valina L, Dawson Ted M
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18308-13. doi: 10.1073/pnas.0606526103. Epub 2006 Nov 20.
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.
核酶聚（ADP - 核糖）聚合酶 -1（PARP -1）的过度激活在多种细胞损伤模型中起着重要作用。在此，我们确定聚（ADP - 核糖）（PAR）聚合物，一种PARP -1活性的产物，为一种先前未被描述的细胞死亡信号。PAR聚合物对神经元具有直接毒性，并且聚（ADP - 核糖）糖苷水解酶（PARG）或磷酸二酯酶1对PAR聚合物的降解可防止PAR聚合物诱导的细胞死亡。通过针对PAR的中和抗体以及PARG的过表达，可降低PARP -1依赖性的皮质神经元NMDA兴奋性毒性。与野生型培养物相比，PARG水平降低的神经元培养物对NMDA兴奋性毒性更敏感。过表达PARG的转基因小鼠在局灶性缺血后梗死体积显著减小。相反，与野生型同窝对照相比，PARG水平降低的小鼠在局灶性缺血后梗死体积显著增加。这些结果揭示PAR聚合物作为一种诱导细胞死亡的信号分子，并表明干扰PAR聚合物信号传导可能为细胞损伤的治疗提供创新的治疗方法。
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