Parthanatos, AIF and PAAN-1 in Neuronal Injury

描述(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。谷氨酸的神经毒性在脑缺血和神经退行性疾病中的重要性已经得到了很好的证明。无论是在体外还是在体内，谷氨酸及其类似物都能通过兴奋毒性机制有效地杀死神经元。聚腺苷二磷酸核糖聚合酶-1(PARP-1)在谷氨酸神经毒性和脑梗塞中起关键作用。先前的研究表明，NO或过氧亚硝酸盐在谷氨酸兴奋毒性和脑梗塞中起着重要作用。在其他反应中，NO或过氧亚硝酸盐可以激活PARP-1，从而通过形成复杂的支化聚(ADP-核糖)(PAR)聚合物而导致细胞死亡。近年来，细胞凋亡诱导因子(AIF)被认为是谷氨酸、活性氧、DNA损伤和PAR聚合物引起的神经毒性的关键介质。AIF驻留在正常健康细胞的线粒体中，但在致命刺激后以PARP-1依赖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。这种形式的细胞死亡最近被指定为副死亡性死亡，以区别于其他类型的细胞死亡，如凋亡、坏死或自噬死亡。在各种模型中，对安乐死级联反应的每一步的干预都被证明是神经保护的。一旦AIF进入细胞核，大规模的DNA断裂(染色质溶解)就会通过特征不佳的机制发生，这很可能是死亡性细胞死亡的执行步骤。因此，有必要通过实验鉴定和鉴定帕金森病AIF相关核酸内切酶-1(PAAN-1)，并探讨PAAN-1在兴奋性毒性和卒中所致神经元损伤中的作用。鉴定AIF相互作用因子和了解PAAN-1在神经元损伤中的作用机制将为终止NO、PAR和AIF的毒性作用提供新的方法，并为神经退行性疾病和卒中的治疗提供创新的治疗途径。

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. This form of cell death has recently been designated parthanatos to distinguish it from other types of cell death such as apoptosis, necrosis or autophagic death. Interference with each step of the parthanatic cascade has been shown to be neuroprotective in a variety of models. Once AIF enters the nucleus, large scale DNA fragmentation (chromatinolysis) occurs through poorly characterized mechanisms, which is likely to be the execution step in parthanatic cell death. Accordingly, experiments are proposed to identify and characterize the parthanatos AIF associated endonuclease-1 (PAAN-1) and to investigate the role of PAAN-1 in excitotoxic and stroke induced neuronal injury. The identification of AIF interactors and understanding the mechanisms of PAAN-1 in neuronal injury will lead to new methods to terminate the toxic actions of NO, PAR and AIF and offer innovative therapeutic approaches to treat neurodegenerative diseases and stroke.