α-突触核蛋白对线粒体膜造成孔道样损伤

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。

α-Synuclein Induce Pore-like Impairments of Mitocondrial Membrane

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 mPTP 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 a diameter 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.