title: Non-Amyloid-β Component of Human α-Synuclein Oligomers Induces Formation of New Aβ Oligomers: Insight into the Mechanisms That Link Parkinson's and Alzheimer's Diseases.
abstract: Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs), of which their major component is the non-amyloid-β component (NAC) of α-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 Aβ 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 Aβ oligomers are still elusive. This work presents the interactions between NAC oligomers and Aβ oligomers at atomic resolution by applying extensive molecular dynamics simulations for an ensemble of cross-seeded NAC-Aβ(1-42) oligomers. The main conclusions of this study are as follows: first, the cross-seeded NAC-Aβ(1-42) oligomers represent polymorphic states, yet NAC oligomers prefer to interact with Aβ(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 β-strands in Aβ(1-42) oligomers, thus leading to new Aβ oligomer structures; and third, NAC oligomers stabilize the cross-β structure of Aβ oligomers, i.e., yielding compact Aβ fibril-like structures.
authors.affiliation: Department of Chemistry, ‡Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev , Beer-Sheva 84105, Israel.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Atsmon-Raz
authors.affiliation: Department of Chemistry, ‡Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev , Beer-Sheva 84105, Israel.
authors.forename: Yifat
authors.initials: Y
authors.lastname: Miller
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D017711:Nonlinear Dynamics; D010300:Parkinson Disease / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D011487:Protein Conformation; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C497604:SNCA protein, human; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; NAC; Parkinson’s disease; amyloid β; amyloids; cross-seeding; peptides; self-assembly; α-synuclein