Supramolecular Modulation of Structural Polymorphism in Pathogenic -Synuclein Fibrils Using Copper(II) Coordination

Structural variation of alpha-synuclein (Syn) fibrils has been linked to the diverse etiologies of synucleinopathies. However, little is known about what specific mechanism provides alpha Syn fibrils with pathologic features. Herein, we demonstrate Cu(II)-based supramolecular approach for unraveling the formation process of pathogenic alpha Syn fibrils and its application in a neurotoxic mechanism study. The conformation of Syn monomer was strained by macrochelation with Cu(II), thereby disrupting the fibril elongation while promoting its nucleation. This non-canonical process formed shortened, beta-sheet enriched alpha Syn fibrils (<0 .2 mu m) that were rapidly transmitted and accumulated to neuronal cells, causing neuronal cell death, in sharp contrast to typical Syn fibrils (ca. 1m). Our approach provided the supramolecular basis for the formation of pathogenic fibrils through physiological factors, such as brain Cu(II).