Poly (ADP-Ribose) and AIF in Neuronal Injury

描述（由申请人提供）：中风和其他神经退行性疾病是导致死亡、残疾和生活质量下降的主要原因。谷氨酸神经毒性在脑缺血和神经退行性疾病中的重要性已得到充分证明。体外和体内施用谷氨酸及其类似物均可通过兴奋毒性机制有效杀死神经元。聚（adp -核糖）聚合酶-1 （PARP-1）在谷氨酸神经毒性和脑梗死中起关键作用。已有研究表明NO或过氧亚硝酸盐在谷氨酸兴奋性毒性和脑梗死中起重要作用。在其他反应中，NO或过氧亚硝酸盐可以激活PARP-1，通过形成复杂和支链聚（adp -核糖）（PAR）聚合物导致细胞死亡。近年来，凋亡诱导因子（apoptosis inducing factor， AIF）被认为是谷氨酸、活性氧、DNA损伤和PAR聚合物引发神经毒性的重要介质。AIF存在于正常健康细胞的线粒体中，但在致命刺激后以依赖PARP-1的方式移动到细胞核。阻止AIF进入细胞核可以使细胞免于死亡。在PARP-1激活后，参与促进线粒体释放AIF的蛋白质和机制尚不清楚。因此，我们建议通过实验来阐明PARP-1激活后AIF释放的潜在分子机制，并研究PAR聚合物在兴奋性毒性和卒中诱导的神经元损伤中的作用。我们希望了解PAR聚合物诱导细胞死亡的机制，AIF的激活以及PAR/AIF信号复合物的其他成分的鉴定将为终止PAR聚合物和AIF的毒性作用提供新的方法，并为治疗神经退行性疾病和中风提供创新的治疗方法。

DESCRIPTION (provided by applicant): Stroke and other neurodegenerative disorders are a leading cause of death, disability and loss of quality of life. The importance of glutamate neurotoxicity in cerebral ischemia and neurodegenerative diseases is well documented. Both in vitro and in vivo administration of glutamate and its analogs effectively kill neurons via excitotoxic mechanisms. Poly(ADP-ribose) polymerase-1 (PARP-1) is pivotal in glutamate neurotoxicity and cerebral infarction. Prior studies indicate that NO, or peroxynitrite plays a prominent role in glutamate excitotoxicity and cerebral infarction. Amongst other responses NO, or peroxynitrite, can activate PARP-1, which leads to cell death through the formation of complex and branched poly(ADP-ribose) (PAR) polymer. Recently, apoptosis inducing factor (AIF) has been identified as key mediator of neurotoxicity triggered by glutamate, reactive oxygen species, DNA damage and PAR polymer. AIF resides in the mitochondria in normal healthy cells, but moves to the nucleus following a lethal stimulus in a PARP-1 dependent manner. Blocking AIF from entering the nucleus can spare cells from death. The proteins and the mechanisms that are involved in facilitating the release of AIF from the mitochondria following PARP-1 activation are not known. Accordingly, experiments are proposed to elucidate the underlying molecular mechanisms accounting for AIF release following PARP-1 activation and to investigate the role of PAR polymer in excitotoxic and stroke induced neuronal injury. We hope that understanding the mechanisms of PAR polymer induced cell death, the activation of AIF and the identification of additional components of the PAR/AIF signaling complex will lead to new methods to terminate the toxic actions of PAR polymer and AIF and offer innovative therapeutic approaches to treat neurodegenerative diseases and stroke. PUBLIC HEALTH RELEVANCE: Stroke and other neurodegenerative disorders are a leading cause of death, disability and loss of quality of life. We hope that understanding the mechanisms of PAR polymer neurotoxic actions in stroke will lead to new methods to terminate the toxic actions of PAR polymer and offer innovative therapeutic approaches to treat neurodegenerative diseases and stroke.