Ruggeri Francesco Simone, Flagmeier Patrick, Kumita Janet R, Meisl Georg, Chirgadze Dimitri Y, Bongiovanni Marie N, Knowles Tuomas P J, Dobson Christopher M
Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
Department of Biochemistry, University of Cambridge, Old Addenbrooke's Site, 80 Tennis Court Road, Cambridge CB2 1GA, United Kingdom.
ACS Nano. 2020 May 26;14(5):5213-5222. doi: 10.1021/acsnano.9b09676. Epub 2020 Mar 17.
Proteinaceous deposits of α-synuclein amyloid fibrils are a hallmark of human disorders including Parkinson's disease. The onset of this disease is also associated with five familial mutations of the gene encoding the protein. However, the mechanistic link between single point mutations and the kinetics of aggregation, biophysical properties of the resulting amyloid fibrils, and an increased risk of disease is still elusive. Here, we demonstrate that the disease-associated mutations of α-synuclein generate different amyloid fibril polymorphs compared to the wild type protein. Remarkably, the α-synuclein variants forming amyloid fibrils of a comparable structure, morphology, and heterogeneity show similar microscopic steps defining the aggregation kinetics. These results demonstrate that a single point mutation can significantly alter the distribution of fibrillar polymorphs in α-synuclein, suggesting that differences in the clinical phenotypes of familial Parkinson's disease could be associated with differences in the mechanism of formation and the structural characteristics of the aggregates.
α-突触核蛋白淀粉样纤维的蛋白质沉积物是包括帕金森病在内的人类疾病的一个标志。这种疾病的发病也与编码该蛋白质的基因的五个家族性突变有关。然而，单点突变与聚集动力学、所得淀粉样纤维的生物物理性质以及疾病风险增加之间的机制联系仍然难以捉摸。在这里，我们证明，与野生型蛋白质相比，α-突触核蛋白的疾病相关突变产生了不同的淀粉样纤维多态性。值得注意的是，形成具有可比结构、形态和异质性的淀粉样纤维的α-突触核蛋白变体显示出定义聚集动力学的相似微观步骤。这些结果表明，单点突变可以显著改变α-突触核蛋白中纤维状多态性的分布，这表明家族性帕金森病临床表型的差异可能与聚集物形成机制和结构特征的差异有关。
