Department of Neurology and Physiology, University of California, San Francisco, California 94158, USA.
J Biol Chem. 2011 Jun 10;286(23):20710-26. doi: 10.1074/jbc.M110.213538. Epub 2011 Apr 13.
The protein α-synuclein has a central role in Parkinson disease, but the mechanism by which it contributes to neural degeneration remains unknown. We now show that the expression of α-synuclein in mammalian cells, including neurons in vitro and in vivo, causes the fragmentation of mitochondria. The effect is specific for synuclein, with more fragmentation by α- than β- or γ-isoforms, and it is not accompanied by changes in the morphology of other organelles or in mitochondrial membrane potential. However, mitochondrial fragmentation is eventually followed by a decline in respiration and neuronal death. The fragmentation does not require the mitochondrial fission protein Drp1 and involves a direct interaction of synuclein with mitochondrial membranes. In vitro, synuclein fragments artificial membranes containing the mitochondrial lipid cardiolipin, and this effect is specific for the small oligomeric forms of synuclein. α-Synuclein thus exerts a primary and direct effect on the morphology of an organelle long implicated in the pathogenesis of Parkinson disease.
α-突触核蛋白在帕金森病中起核心作用，但它导致神经退行性变的机制尚不清楚。我们现在表明，α-突触核蛋白在哺乳动物细胞中的表达，包括体外和体内的神经元，会导致线粒体碎片化。这种效应是特异性的，α-突触核蛋白比β-或γ-异构体引起的碎片化更多，并且不会伴随着其他细胞器形态或线粒体膜电位的变化。然而，线粒体碎片化最终会导致呼吸作用下降和神经元死亡。这种碎片化不需要线粒体分裂蛋白 Drp1，并且涉及突触核蛋白与线粒体膜的直接相互作用。在体外，突触核蛋白使含有线粒体脂质心磷脂的人工膜碎片化，并且这种效应是突触核蛋白的小寡聚形式特异性的。因此，α-突触核蛋白对一种细胞器的形态产生了主要和直接的影响，这种细胞器长期以来一直被认为与帕金森病的发病机制有关。
