Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, 305-764, Republic of Korea.
Sci Rep. 2019 Jan 11;9(1):59. doi: 10.1038/s41598-018-37276-1.
The α-synuclein is a major component of amyloid fibrils found in Lewy bodies, the characteristic intracellular proteinaceous deposits which are pathological hallmarks of neurodegenerative diseases such as Parkinson's disease (PD) and dementia. It is an intrinsically disordered protein that may undergo dramatic structural changes to form amyloid fibrils. Aggregation process from α-synuclein monomers to amyloid fibrils through oligomeric intermediates is considered as the disease-causative toxic mechanism. However, mechanism underlying aggregation is not well-known despite several attempts. To characterize the mechanism, we have explored the effects of pH and temperature on the structural properties of wild-type and mutant α-synuclein using molecular dynamics (MD) simulation technique. MD studies suggested that amyloid fibrils can grow by monomer. Conformational transformation of the natively unfolded protein into partially folded intermediate could be accountable for aggregation and fibrillation. An intermediate α-strand was observed in the hydrophobic non-amyloid-β component (NAC) region of α-synuclein that could proceed to α-sheet and initiate early assembly events. Water network around the intermediate was analyzed to determine its influence on the α-strand structure. Findings of this study provide novel insights into possible mechanism of α-synuclein aggregation and promising neuroprotective strategy that could aid alleviate PD and its symptoms.
α-突触核蛋白是路易小体（Lewy bodies）中发现的淀粉样纤维的主要成分，路易小体是神经退行性疾病（如帕金森病（PD）和痴呆症）的特征性细胞内蛋白沉积物。它是一种固有无序的蛋白质，可能会发生剧烈的结构变化形成淀粉样纤维。从α-突触核蛋白单体通过寡聚体中间体到淀粉样纤维的聚集过程被认为是疾病致病的毒性机制。然而，尽管已经进行了多次尝试，但聚合的机制仍不清楚。为了研究该机制，我们使用分子动力学（MD）模拟技术探索了 pH 值和温度对野生型和突变型α-突触核蛋白结构特性的影响。MD 研究表明，淀粉样纤维可以通过单体生长。天然无规卷曲蛋白向部分折叠中间态的构象转变可能是聚集和纤维化的原因。在α-突触核蛋白的疏水性非淀粉样β成分（NAC）区域观察到中间态的α-链，它可以进一步形成α-折叠并引发早期组装事件。分析了中间态周围的水分子网络，以确定其对α-链结构的影响。这项研究的结果为α-突触核蛋白聚集的可能机制提供了新的见解，并为缓解帕金森病及其症状提供了有前景的神经保护策略。
