TY - JOUR
T1 - Assembly of α-synuclein aggregates on phospholipid bilayers
AU - Lv, Zhengjian
AU - Hashemi, Mohtadin
AU - Banerjee, Siddhartha
AU - Zagorski, Karen
AU - Rochet, Jean Christophe
AU - Lyubchenko, Yuri L.
N1 - Funding Information:
The work at the University of Nebraska Medical Center (UNMC) was supported by grants from the National Institutes of Health to Y.L.L. ( R01 GM096039 , R01GM118006 and R21 NS101504 ). J.C.R. was supported by the Branfman Family Foundation . M.H. was partially supported by the UNMC Graduate Fellowship. The computational modeling was partially performed using resources at the Holland Computing Center of the University of Nebraska, which receives support from the Nebraska Research Initiative . Anton 2 computer time was provided by the Pittsburgh Supercomputing Center (PSC) through Grant R01GM116961 from the National Institutes of Health. The Anton 2 machine at PSC was generously made available by D.E. Shaw Research. The authors thank Melody A. Montgomery for the professional editing of the manuscript.
Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2019/9
Y1 - 2019/9
N2 - The spontaneous self-assembly of α-synuclein (α-syn) into aggregates of different morphologies is associated with the development of Parkinson's disease. However, the mechanism behind the spontaneous assembly remains elusive. The current study shows a novel effect of phospholipid bilayers on the assembly of the α-syn aggregates. Using time-lapse atomic force microscopy, it was discovered that α-syn assembles into aggregates on bilayer surfaces, even at the nanomolar concentration range. The efficiency of the aggregation process depends on the membrane composition, with the greatest efficiency observed for of 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS). Importantly, assembled aggregates can dissociate from the surface, suggesting that on-surface aggregation is a mechanism by which pathological aggregates may be produced. Computational modeling revealed that dimers of α-syn assembled rapidly, through the membrane-bound monomer on POPS bilayer, due to an aggregation-prone orientation of α-syn. Interaction of α-syn with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) leads to a binding mode that does not induce a fast assembly of the dimer. Based on these findings, we propose a model in which the interaction of α-syn with membranes plays a critical role initiating the formation of α-syn aggregates and the overall aggregation process.
AB - The spontaneous self-assembly of α-synuclein (α-syn) into aggregates of different morphologies is associated with the development of Parkinson's disease. However, the mechanism behind the spontaneous assembly remains elusive. The current study shows a novel effect of phospholipid bilayers on the assembly of the α-syn aggregates. Using time-lapse atomic force microscopy, it was discovered that α-syn assembles into aggregates on bilayer surfaces, even at the nanomolar concentration range. The efficiency of the aggregation process depends on the membrane composition, with the greatest efficiency observed for of 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS). Importantly, assembled aggregates can dissociate from the surface, suggesting that on-surface aggregation is a mechanism by which pathological aggregates may be produced. Computational modeling revealed that dimers of α-syn assembled rapidly, through the membrane-bound monomer on POPS bilayer, due to an aggregation-prone orientation of α-syn. Interaction of α-syn with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) leads to a binding mode that does not induce a fast assembly of the dimer. Based on these findings, we propose a model in which the interaction of α-syn with membranes plays a critical role initiating the formation of α-syn aggregates and the overall aggregation process.
KW - Amyloid aggregation
KW - Computer modeling
KW - Lipid bilayer
KW - Parkinson's disease
KW - Time-lapse AFM
KW - α-synuclein
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U2 - 10.1016/j.bbapap.2019.06.006
DO - 10.1016/j.bbapap.2019.06.006
M3 - Article
C2 - 31226488
AN - SCOPUS:85067846397
SN - 1570-9639
VL - 1867
SP - 802
EP - 812
JO - BBA - Protein Structure
JF - BBA - Protein Structure
IS - 9
ER -