Direct Membrane Association Drives Mitochondrial Fission by the Parkinson Disease-associated Protein α-Synuclein
Direct Membrane Association Drives Mitochondrial Fission by the Parkinson Disease-associated Protein α-Synuclein
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DOI：
10.1074/jbc.m110.213538
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发表时间：
2011-06-10
影响因子：
4.8
通讯作者：
Edwards, Robert H.
中科院分区：
文献类型：
--
作者：
Nakamura, Ken;Nemani, Venu M.;Edwards, Robert H.
蛋白质α-突触核蛋白在帕金森病中起着核心作用，但它导致神经变性的机制仍然未知。我们现在表明，α-突触核蛋白在哺乳动物细胞，包括神经元在体外和体内的表达，导致线粒体的碎片。这种效应对突触核蛋白是特异性的，α-比β-或γ-亚型的片段化更多，并且不伴有其他细胞器形态或线粒体膜电位的变化。然而，线粒体片段化最终导致呼吸下降和神经元死亡。片段化不需要线粒体分裂蛋白Drp 1，并且涉及突触核蛋白与线粒体膜的直接相互作用。在体外，突触核蛋白片段人工膜含有线粒体脂质心磷脂，这种效果是特定的小寡聚体形式的突触核蛋白。因此，α-突触核蛋白对长期参与帕金森病发病机制的细胞器的形态发挥主要和直接的作用。
The protein alpha-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 alpha-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 alpha- than beta- or gamma-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. alpha-Synuclein thus exerts a primary and direct effect on the morphology of an organelle long implicated in the pathogenesis of Parkinson disease.