Department of Biochemistry and Molecular Biology, The Institute for Medical Research, Israel-Canada, Hebrew University, Jerusalem 91120, Israel.
J Biol Chem. 2010 Mar 5;285(10):7334-43. doi: 10.1074/jbc.M109.061051. Epub 2010 Jan 6.
Alpha-synuclein (alphaS) is a protein involved in the cytopathology and genetics of Parkinson disease and is thought to affect mitochondrial complex I activity. Previous studies have shown that mitochondrial toxins and specifically inhibitors of complex I activity enhance alphaS pathogenesis. Here we show that alphaS overexpression specifically inhibits complex I activity in dopaminergic cells and in A53T alphaS transgenic mouse brains. Importantly, our results indicate that the inhibitory effect on complex I activity is not associated with alphaS-related pathology. Specifically, complex I activity measured in purified mitochondria from A53T alphaS transgenic mouse brains was not affected by mouse age; Parkinson disease-like symptoms; levels of alphaS soluble oligomers; levels of insoluble, lipid-associated alphaS; or alphaS intraneuronal depositions in vivo. Likewise, no correlation was found between complex I activity and polyunsaturated fatty acid-induced alphaS depositions in Lewy body-like inclusions in cultured dopaminergic cells. We further show that the effect of alphaS on complex I activity is not due to altered mitochondrial protein levels or affected complex I assembly. Based on the results herein, we suggest that alphaS expression negatively regulates complex I activity as part of its normal, physiological role.
α-突触核蛋白（αS）参与帕金森病的细胞病理学和遗传学，被认为影响线粒体复合物 I 的活性。先前的研究表明，线粒体毒素，特别是复合物 I 活性的抑制剂，增强了αS 的发病机制。在这里，我们表明αS 过表达特异性抑制多巴胺能细胞和 A53TαS 转基因小鼠脑中的复合物 I 活性。重要的是，我们的结果表明，对复合物 I 活性的抑制作用与αS 相关的病理学无关。具体来说，从 A53TαS 转基因小鼠脑中分离出的纯化线粒体中，复合物 I 活性不受小鼠年龄、帕金森病样症状、αS 可溶性寡聚物水平、不溶性、脂相关αS 水平或体内αS 神经元内沉积的影响。同样，在培养的多巴胺能细胞中的路易体样包涵体中，多不饱和脂肪酸诱导的αS 沉积与复合物 I 活性之间也没有相关性。我们进一步表明，αS 对复合物 I 活性的影响不是由于线粒体蛋白水平的改变或复合物 I 组装受到影响。基于本文的结果，我们认为αS 表达作为其正常生理功能的一部分，负调节复合物 I 活性。
