Parthanatos（PARP-1依赖性死亡）在线粒体功能障碍所致帕金森氏病神经元死亡中的作用及机制研究

Parkinson’s disease is a common type of neurodegenerative disease which often occurs in old people. Although no effective therapy could be used, mitochondrial dysfunction has been found to be a crucial factor responsible for its initiation and development. Parthanatos is a newly-established mode of programmed cell death characterized by hyper-activation of PARP-1 and cytoplasmic accumulation of PAR. We found that the death of SH-SY5Y cells induced by rotenone, an inhibitor of mitochondrial respiratory chain, was accompanied with over-expression of PARP-1 and excessive generation of PAR. We thus hypothesize that the neuronal death due to mitochondrial dysfunction is closely associated with the activation of parthanatos. In this project, we will investigate the following issues to clarify the roles of PARP-1 and PAR in rotenone-induced neuronal death: (1) The mechanism underlying the hyper-activation of PARP-1 induced by rotenone; (2) The effect on rotenone of PARG and ARH3 which could degrade PAR; (3) The mechanism accounting for the influence of PARP-1 and PAR on neuronal glucose metabolism.

帕金森氏病是常见的神经系统退行性病变。虽然缺乏有效的治疗方法，但已发现线粒体功能障碍是其主要的病理基础。Parthanatos是一种以PARP-1过度激活和细胞中PAR积聚为特征的新型程序性细胞死亡方式。我们发现线粒体呼吸链阻断剂鱼藤酮诱导SH-SY5Y细胞死亡的过程伴发有PARP-1的过度表达以及细胞中PAR的积聚，进而提出科学假说“线粒体功能障碍诱导的神经元死亡与Parthanatos的激活密切相关”。在本项目中，我们延续以往的研究，从以下方面探讨PARP-1和PAR在鱼藤酮诱导神经元死亡过程中的作用和机制：（1）鱼藤酮诱导PARP-1过度激活的机制；（2）鱼藤酮对细胞内PAR降解酶PARG和ARH3的影响和机制；（3）PARP-1和PAR对神经元糖代谢的影响及机制。我们期望通过本研究，阐明Parthanatos在线粒体功能障碍所致神经元死亡中的作用和机制。

帕金森氏病是常见的神经系统退行性病变。虽然缺乏有效的治疗方法，但已发现线粒体功能障碍是其主要的病理基础。Parthanatos是一种以PARP-1过度激活和细胞中PAR积聚为特征的新型程序性细胞死亡方式。我们发现线粒体呼吸链阻断剂鱼藤酮诱导SH-SY5Y细胞死亡的过程伴发有PARP-1的过度表达以及细胞中PAR的积聚，进而提出科学假说“线粒体功能障碍诱导的神经元死亡与Parthanatos的激活密切相关”。在本项目中，我们延续以往的研究，从以下方面探讨PARP-1和PAR在鱼藤酮诱导神经元死亡过程中的作用和机制：（1）鱼藤酮诱导PARP-1过度激活的机制；（2）鱼藤酮对细胞内PAR降解酶PARG和ARH3的影响及机制；（3）PARP-1和PAR对神经元糖代谢的影响及机制。我们期望通过本研究，阐明Parthanatos在线粒体功能障碍所致神经元死亡中的作用和机制。