Parthanatos, AIF and PAAN-1 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。这种形式的细胞死亡最近被命名为parthanatos，以区别于其他类型的细胞死亡，如凋亡、坏死或自噬性死亡。在各种模型中，干扰旁突级联的每个步骤已被证明具有神经保护作用。一旦AIF进入细胞核，大规模的DNA断裂（染色质溶解）通过尚未明确的机制发生，这可能是旁细胞死亡的执行步骤。因此，我们提出了鉴定和表征parthanatos AIF相关内切酶-1 （PAAN-1）的实验，并探讨PAAN-1在兴奋性毒性和卒中诱导的神经元损伤中的作用。发现AIF相互作用物，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脑卒中的治疗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. 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.