期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：8
页码：4125-4130
DOI：10.1073/pnas.1921702117
出版社：The National Academy of Sciences of the United States of America
摘要：Filaments made up of different isoforms of tau protein are associated with a variety of neurodegenerative diseases. Filaments made up of the 4R-tau isoform, which has four repeat regions (R1 to R4), are found in patients suffering from Alzheimer’s disease, while filaments made of the 3R-tau isoform, which contains only three repeat units (R1, R3, and R4), are found in patients with Pick’s disease (frontotemporal dementia). In this work, a predictive coarse-grained protein force field, the associative memory water-mediated structure and energy model (AWSEM), is used to study the energy landscapes of nucleation of the two different fibrils derived from patients with Pick’s and Alzheimer’s diseases. The landscapes for nucleating both fibril types contain amorphous oligomers leading to branched structures as well as prefibrillar oligomers. These two classes of oligomers differ in their structural details: The prefibrillar oligomers have more parallel in-register β-strands, which ultimately lead to amyloid fibrils, while the amorphous oligomers are characterized by a near random β-strand stacking, leading to a distinct amorphous phase. The landscape topography suggests that there must be significant structural reordering, or “backtracking,” to transit from the amorphous aggregation channel to the fibrillization channel. Statistical mechanical perturbation theory allows us to evaluate the effects of changing concentration on the aggregation free-energy landscapes and to predict the effects of phosphorylation, which is known to facilitate the aggregation of tau repeats.
