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Supramolecular Modulation of Structural Polymorphism in Pathogenic α‐Synuclein Fibrils Using Copper(II) Coordination
Author(s) -
Choi Tae Su,
Lee Jeeyoung,
Han Jong Yoon,
Jung Byung Chul,
Wongkongkathep Piriya,
Loo Joseph A.,
Lee Min Jae,
Kim Hugh I.
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201712286
Subject(s) - fibril , supramolecular chemistry , chemistry , synucleinopathies , biophysics , monomer , crystallography , fibrillogenesis , nucleation , mutant , alpha synuclein , biochemistry , crystal structure , biology , polymer , gene , parkinson's disease , medicine , pathology , disease , organic chemistry
Structural variation of α‐synuclein (αSyn) fibrils has been linked to the diverse etiologies of synucleinopathies. However, little is known about what specific mechanism provides αSyn fibrils with pathologic features. Herein, we demonstrate Cu(II)‐based supramolecular approach for unraveling the formation process of pathogenic αSyn fibrils and its application in a neurotoxic mechanism study. The conformation of αSyn monomer was strained by macrochelation with Cu(II), thereby disrupting the fibril elongation while promoting its nucleation. This non‐canonical process formed shortened, β‐sheet enriched αSyn fibrils (<0.2 μm) that were rapidly transmitted and accumulated to neuronal cells, causing neuronal cell death, in sharp contrast to typical αSyn fibrils (ca. 1 μm). Our approach provided the supramolecular basis for the formation of pathogenic fibrils through physiological factors, such as brain Cu(II).