α-突触核蛋白对线粒体膜造成孔道样损伤  

α-Synuclein Induces Pore-like Impairments of Mitochondrial Membrane

作　　者：汪志鹏[1,2] 高歌 段春礼[1,2] 杨慧 WANG Zhi-Peng;GAO Ge;DUAN Chun-Li;YANG Hui(Department of Neurology,School of Basic Science and Medicine,Capital Medical University,Center for Parkinson＇s Disease,Beifing Institute for Brain Disorders,Key Laboratory for Neurodegenerative Disease of the Ministry of Education,Beijing 100069,China)

机构地区：[1]首都医科大学基础医学院神经生物学系 [2]北京脑重大疾病研究院帕金森病研究所教育部神经变性病重点实验室,北京100069

出　　处：《中国生物化学与分子生物学报》2018年第9期1013-1020,共8页Chinese Journal of Biochemistry and Molecular Biology

基　　金：国家重点研究发展计划(No.2016YFC1306000); 国家自然科学基金(No.81371398,No.81371200); 北京市自然科学基金(No.7131001)资助

摘　　要：α-突触核蛋白(α-synuclein,α-syn)作为第一个发现的帕金森病(Parkinson’s disease,PD)致病基因,在PD发生发展过程中具有重要作用。尽管有研究发现,α-syn对线粒体功能有损伤作用,但其对线粒体膜的损害机制尚不明确。本实验旨在探究α-syn对线粒体膜形态的影响,并找到更加微观的方式观察线粒体膜的变化。Thy-1-α-syn转基因动物与野生型动物相比,线粒体膜电势降低17%(P<0.01),膜通透性增加20.5%(P<0.01),转基因组线粒体细胞色素C释放增多64%(P<0.01),这有可能引起线粒体自噬和细胞凋亡。原子力显微镜结果显示,野生型小鼠脑组织线粒体表面光滑,α-syn转基因小鼠脑组织线粒体表面发现有锯齿状改变,而且在过表达α-syn的原代神经元线粒体膜表面有许多小凹陷,出现口径60~200 nm,深达20~60 nm的孔道。这可能是α-syn对线粒体膜造成的孔道样损伤。过表达α-syn全长组和N端组的原代神经元电镜结果显示,线粒体膜被破坏,并且出现空泡样线粒体和自噬小泡。本研究发现,过表达α-syn可能在线粒体表面形成孔道样改变,α-syn的N端是引起线粒体膜损伤主要结构域。As the first pathogenic gene of Parkinson＇s disease（ PD）,α-synuclein（ α-syn） was found to play an important role in the development of PD. Although studies have found that α-syn has damage effect on mitochondria,its mechanism of damage to the mitochondrial membrane is not yet clear. The purpose of this study was to investigate the effect of α-syn on the morphology of the mitochondrial membrane and to find more microscopic observations of mitochondrial membrane changes. The mitochondrial membrane potential was decreased by 17%（ P 〈0. 01）,and the m PTP opening was increased by 20. 5%（ P〈 0. 01） in α-syn transgenic animals as compared with the wild type animals.Moreover,the release of mitochondrial cytochrome-C in the transgenic group（ P 〈0. 01） was increased by 64%,which might lead to mitophagy and apoptosis. Atomic force microscopy（ AFM） showed that the surface of mitochondrial membrane of α-syn transgenic group is unsmooth. After overexpression of α-syn in primary neurons,there are many small pores on the mitochondrial membrane,and the pores with adiameter of 60-200 nm and a depth of 20-60 nm might be caused by α-syn. The primary neurons overexpressing full-length and N-terminal of α-syn were observed by transmission electron microscope and vacuolar mitochondria and autophagy vesicles were detected,which indicated that the N-terminal of α-syn caused the damage of mitochondria. This study found that overexpression N-terminal of α-syn could induce pore-like damage on the mitochondrial membrane.

关 键 词：帕金森病 Α-突触核蛋白 α-syn N端结构域 线粒体膜损伤 原子力显微镜 

分 类 号：R34[医药卫生—基础医学]