期刊
ACS CHEMICAL NEUROSCIENCE
卷 7, 期 1, 页码 46-55出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.5b00204
关键词
Parkinson's disease; NAC; amyloids; self-assembly; peptides; cross-seeding Alzheimer's disease; amyloid beta; alpha-synuclein
资金
- FP7-PEOPLE-CIG Marie Curie Career Integration Grant [303741]
Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs), of which their major component is the non-amyloid-beta component (NAC) of alpha-synuclein (AS). Clinical studies have identified a link between PD and Alzheimer's disease (AD), but the question of why PD patients are at risk to develop various types of dementia, such as AD, is still elusive. In vivo studies have shown that A beta can act as a seed for NAC/AS aggregation, promoting NAC/AS aggregation and thus contributing to the etiology of PD. However, the mechanisms by which NAC/AS oligomers interact with A beta oligomers are still elusive. This work presents the interactions between NAC oligomers and A beta oligomers at atomic resolution by applying extensive molecular dynamics simulations for an ensemble of cross-seeded NAC-A beta(1-42) oligomers. The main conclusions of this study are as follows: first, the cross-seeded NAC-A beta(1-42) oligomers represent polymorphic states, yet NAC oligomers prefer to interact with A beta(1-42) oligomers to form double-layer over single-layer conformations due to electrostatic/hydrophobic interactions; second, among the single-layer conformations, the NAC oligomers induce formation of new beta-strands in A beta(1-42) oligomers, thus leading to new A beta oligomer structures; and third, NAC oligomers stabilize the cross-beta structure of A beta oligomers, i.e., yielding compact A beta fibril-like structures.
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