biostudies-literatureZacharopoulou MCambridge TrustVersus ArthritisGeorge and Marie Vergottis FoundationUniversity of ExeterAlzheimer?s Research UKRoyal SocietyUK Research and InnovationEngineering and Physical Sciences Research CouncilNewnham College, University of CambridgeEuropean Research CouncilNational Biofilms Innovation CentreMedical Research CouncilInfinitus China Ltd.Wellcome TrustUniversity of CambridgeMichael J. Fox Foundation for Parkinson's Research13131-13145https://www.ebi.ac.uk/biostudies/studies/S-EPMC12023029biostudies-literatureUnknown147(16)Parkinson's disease (PD) is linked to the aggregation of the intrinsically disordered protein α-synuclein (aSyn), but the precise triggers and mechanisms driving this process remain unclear. Local environmental factors, such as ion concentrations, can influence aSyn's conformational ensemble and its tendency to aggregate. In this study, we explore how physiologically relevant ions, mainly Ca²⁺ and Na⁺, affect aSyn aggregation, monomer structural dynamics, and fibril polymorphism. ThT fluorescence assays show that all ions speed up aggregation, with Ca²⁺ having the strongest effect. Using heteronuclear single quantum correlation nuclear magnetic resonance (¹H-¹⁵N HSQC NMR) spectroscopy, we validate that Ca²⁺ binds at the C-teJournal of the American Chemical SocietyLocal Ionic Conditions Modulate the Aggregation Propensity and Influence the Structural Polymorphism of α-Synuclein.PMC12023029022159MR/K02292X/1MR/T02223X/116238ARUK-PG013-14819644BB/R012415/1 03PoC20-105URF/R1/221795EP/W022842/1065807/Z/01/Z203249/Z/16/ZStephens ADDai WFusco GMcCoy TMDe Simone AZacharopoulou MPhillips JJMartel AMela IKaminski Schierle GSRouth AFRoss JFernandez-Villegas ASeetaloo NfalseLocal Ionic Conditions Modulate the Aggregation Propensity and Influence the Structural Polymorphism of α-Synuclein.Parkinson's disease (PD) is linked to the aggregation of the intrinsically disordered protein α-synuclein (aSyn), but the precise triggers and mechanisms driving this process remain unclear. Local environmental factors, such as ion concentrations, can influence aSyn's conformational ensemble and its tendency to aggregate. In this study, we explore how physiologically relevant ions, mainly Ca²⁺ and Na⁺, affect aSyn aggregation, monomer structural dynamics, and fibril polymorphism. ThT fluorescence assays show that all ions speed up aggregation, with Ca²⁺ having the strongest effect. Using heteronuclear single quantum correlation nuclear magnetic resonance (¹H-¹⁵N HSQC NMR) spectroscopy, we validate that Ca²⁺ binds at the C-te2025-01-01T00:00:00Z2025 Apr2026-06-02T04:12:45.089Z2026-04-14T03:13:14.907ZS-EPMC120230294020767110.1021/jacs.4c13473