Structural Insights of Fe³⁺ Induced α-synuclein Fibrillation in Parkinson's Disease

Amyloid aggregation of α-synuclein (α-syn) in Lewy bodies (LBs) is the pathological hallmark of Parkinson's disease (PD). Iron, especially Fe³⁺, is accumulated in substantia nigra of PD patients and co-deposited with α-syn in LBs. However, how Fe³⁺ modulates α-syn fibrillation at molecular level remains unclear. In this study, we found that Fe³⁺ can promote α-syn fibrillation at low concentration while inhibit its fibrillation at high concentration. NMR titration study shows poor interaction between α-syn monomer and Fe³⁺. Instead, we found that Fe³⁺ binds to α-syn fibrils. By using cryo-electron microscopy (cryo-EM), we further determined the atomic structure of α-syn fibril in complex with Fe³⁺ at the resolution of 2.7 Å. Strikingly, two extra electron densities adjacent to His50 and Glu57 were observed as putative binding sites of Fe³⁺ and water molecules, suggesting that Fe³⁺ binds to the negative cleft of the fibril and stabilizes the fibril structure for promoting α-syn aggregation. Further mutagenesis study shows mutation of His50 abolishes the Fe³⁺-facilitated fibrillation of α-syn. Our work illuminates the structural basis of the interaction of Fe³⁺ and α-syn in both monomeric and fibrillar forms, and sheds light on understanding the pathological role of Fe³⁺ in α-syn aggregation in PD.