Structural Insights of Fe 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 Fe, is accumulated in substantia nigra of PD patients and co-deposited with α-syn in LBs. However, how Fe modulates α-syn fibrillation at molecular level remains unclear. In this study, we found that Fe 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 Fe. Instead, we found that Fe 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 Fe at the resolution of 2.7 Å. Strikingly, two extra electron densities adjacent to His50 and Glu57 were observed as putative binding sites of Fe and water molecules, suggesting that Fe 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 Fe-facilitated fibrillation of α-syn. Our work illuminates the structural basis of the interaction of Fe and α-syn in both monomeric and fibrillar forms, and sheds light on understanding the pathological role of Fe in α-syn aggregation in PD.