Ibrahim Tarek, McLaurin JoAnne
Biological Sciences, Sunnybrook Research Institute, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, M4N 3M5, ON, Canada.
Biological Sciences, Sunnybrook Research Institute, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, M4N 3M5, ON, Canada.
Biochem Biophys Res Commun. 2016 Jan 15;469(3):529-34. doi: 10.1016/j.bbrc.2015.12.043. Epub 2015 Dec 15.
Recent literature demonstrates the accelerated aggregation of α-synuclein, a protein implicated in the pathogenesis of Parkinson's disease (PD), by the presence of preformed fibrillar conformers in vitro. Furthermore, these preformed fibrillar seeds are suggested to accelerate pathological induction in vivo when injected into the brains of mice. Variation in the results of in vivo studies is proposed to be caused by α-synuclein conformational variants. To investigate the impact of amino acid sequence on seeding efficiency, human and mouse α-synuclein seeds, which vary at 7 amino acid residues, were generated and cross-seeding kinetics studied. Using transmission electron microscopy (TEM), we confirmed that mouse α-synuclein aggregated more rapidly than human α-synuclein. Subsequently, we determined that seeding of human and mouse α-synuclein was more rapid in the presence of seeds generated from the same species. In addition, an established amyloid inhibitor, scyllo-inositol, was examined for potential inhibitory effects on α-synuclein aggregation. TEM analysis of protein:inhibitor assays demonstrated that scyllo-inositol inhibits the aggregation of α-synuclein, suggesting the therapeutic potential of the small molecule in PD.
近期文献表明，在体外，帕金森病（PD）发病机制中涉及的一种蛋白质α-突触核蛋白，会因预先形成的纤维状构象异构体的存在而加速聚集。此外，当将这些预先形成的纤维状种子注射到小鼠大脑中时，它们会在体内加速病理诱导。体内研究结果的差异被认为是由α-突触核蛋白构象变体引起的。为了研究氨基酸序列对种子生成效率的影响，我们生成了在7个氨基酸残基处存在差异的人源和小鼠源α-突触核蛋白种子，并研究了交叉种子生成动力学。使用透射电子显微镜（TEM），我们证实小鼠α-突触核蛋白的聚集速度比人α-突触核蛋白更快。随后，我们确定在存在同物种生成的种子的情况下，人源和小鼠源α-突触核蛋白的种子生成速度更快。此外，我们还研究了一种已确定的淀粉样蛋白抑制剂——异肌醇，对α-突触核蛋白聚集的潜在抑制作用。蛋白质与抑制剂分析的TEM结果表明，异肌醇可抑制α-突触核蛋白的聚集，这表明该小分子在帕金森病治疗方面具有潜力。
