Sideroflexin 3 is an α-synuclein-dependent mitochondrial protein that regulates synaptic morphology.
Sideroflexin 3 is an α-synuclein-dependent mitochondrial protein that regulates synaptic morphology.
复制标题
Sideroflexin 3是一种调节突触形态的α-突触核蛋白依赖性线粒体蛋白。
DOI：
10.1242/jcs.194241
复制
发表时间：
2017-01-15
影响因子：
4
通讯作者：
Gillingwater TH
中科院分区：
文献类型：
--
作者：
Amorim IS;Graham LC;Carter RN;Morton NM;Hammachi F;Kunath T;Pennetta G;Carpanini SM;Manson JC;Lamont DJ;Wishart TM;Gillingwater TH
α-突触核蛋白在帕金森氏病中起着核心作用，它导致突触容易变性。然而，α-突触核蛋白控制突触稳定性和变性的下游机制尚不完全清楚。在这里，对从α-突触核蛋白−/−小鼠脑中分离出的突触进行比较蛋白质组学研究，确定线粒体蛋白是α-突触核蛋白的主要靶点，揭示了37种以前与α-突触核蛋白或神经退行性变途径无关的线粒体蛋白。其中，铁弹性蛋白3(SFXN3)是一种定位于线粒体内膜的线粒体蛋白。SFXN3的缺失没有干扰小鼠突触中线粒体电子传输链的功能，这表明它在线粒体中的功能可能不依赖于典型的生物能量途径。相比之下，对SFXN3水平的实验性操作扰乱了果蝇神经肌肉接头的突触形态。这些结果为α-突触核蛋白依赖途径提供了新的见解，突出了对突触线粒体蛋白的重要影响，包括SFXN3。我们还鉴定了SFXN3是一种新的线粒体蛋白，能够在体内调节突触的形态。摘要：比较蛋白质组学显示线粒体蛋白是α-突触核蛋白的主要靶点。铁弹性蛋白3是一种依赖α突触核蛋白的线粒体蛋白，能够在体内改变突触形态。
α-Synuclein plays a central role in Parkinson's disease, where it contributes to the vulnerability of synapses to degeneration. However, the downstream mechanisms through which α-synuclein controls synaptic stability and degeneration are not fully understood. Here, comparative proteomics on synapses isolated from α-synuclein−/− mouse brain identified mitochondrial proteins as primary targets of α-synuclein, revealing 37 mitochondrial proteins not previously linked to α-synuclein or neurodegeneration pathways. Of these, sideroflexin 3 (SFXN3) was found to be a mitochondrial protein localized to the inner mitochondrial membrane. Loss of SFXN3 did not disturb mitochondrial electron transport chain function in mouse synapses, suggesting that its function in mitochondria is likely to be independent of canonical bioenergetic pathways. In contrast, experimental manipulation of SFXN3 levels disrupted synaptic morphology at the Drosophila neuromuscular junction. These results provide novel insights into α-synuclein-dependent pathways, highlighting an important influence on mitochondrial proteins at the synapse, including SFXN3. We also identify SFXN3 as a new mitochondrial protein capable of regulating synaptic morphology in vivo. Summary: Comparative proteomics revealed that mitochondrial proteins are a major target for α-synuclein. Sideroflexin 3 (SFXN3) was identified as one α-synuclein-dependent mitochondrial protein capable of altering synaptic morphology in vivo.