Supramolecular Modulation of Structural Polymorphism in Pathogenic α‐Synuclein Fibrils Using Copper(II) Coordination
[1];
[1]
- Department of Chemistry Korea University Seoul 02841 Republic of Korea
- Department of Biomedical Sciences, Neuroscience Research Institute Seoul National University College of Medicine Seoul 03080 Republic of Korea
- Department of Chemistry and Biochemistry University of California-Los Angeles Los Angeles CA 90095 USA, Systems Biology Center, Research Affairs Faculty of Medicine Chulalongkorn University Bangkok 10330 Thailand
- Department of Chemistry and Biochemistry University of California-Los Angeles Los Angeles CA 90095 USA, Department of Biological Chemistry David Geffen School of Medicine University of California-Los Angeles Los Angeles CA 90095 USA, UCLA Molecular Biology Institute UCLA/DOE Institute for Genomics and Proteomics University of California-Los Angeles Los Angeles CA 90095 USA
Abstract 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).
- Sponsoring Organization:
- USDOE
- Grant/Contract Number:
- FC02-02ER63421
- OSTI ID:
- 1421571
- Journal Information:
- Angewandte Chemie (International Edition), Journal Name: Angewandte Chemie (International Edition) Vol. 57 Journal Issue: 12; ISSN 1433-7851
- Publisher:
- Wiley Blackwell (John Wiley & Sons)Copyright Statement
- Country of Publication:
- Germany
- Language:
- English
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