Poly(ADP-ribose) (PAR) polymer is a death signal
Poly(ADP-ribose) (PAR) polymer is a death signal
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DOI：
10.1073/pnas.0606526103
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发表时间：
2006-11-28
影响因子：
11.1
通讯作者：
Dawson, Ted M.
中科院分区：
文献类型：
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作者：
Andrabi, Shaida A.;Kim, No Soo;Dawson, Ted M.
核酶聚（ADP-核糖）聚合酶-1（PARP-1）的过度活化在各种细胞损伤模型中起着重要作用。在这里，我们确定聚（ADP-核糖）（PAR）聚合物，PARP-1活性的产物，作为一个以前未表征的细胞死亡信号。PAR聚合物对神经元具有直接毒性，聚（ADP-核糖）糖水解酶（PARG）或磷酸二酯酶1降解PAR聚合物可防止PAR聚合物诱导的细胞死亡。通过PAR中和抗体和PARG过表达降低皮质神经元的PARP-1依赖性NMDA兴奋性毒性。PARG水平降低的神经元培养物比WT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显著减少了梗死体积。相反，与WT同窝对照组相比，PARG水平降低的小鼠在局灶性缺血后梗死体积显著增加。这些结果揭示了PAR聚合物作为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治疗细胞损伤提供创新的治疗方法。
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.