@article{c0469a1f17fc46dc99bafc2b7bd7d66e,
title = "Supramolecular Modulation of Structural Polymorphism in Pathogenic α-Synuclein Fibrils Using Copper(II) Coordination",
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).",
keywords = "Parkinson's disease, fibril strain, mass spectrometry, small-angle X-ray scattering, transition metals",
author = "Choi, {Tae Su} and Jeeyoung Lee and Han, {Jong Yoon} and Jung, {Byung Chul} and Piriya Wongkongkathep and Loo, {Joseph A.} and Lee, {Min Jae} and Kim, {Hugh I.}",
note = "Funding Information: [*] T. S. Choi, J. Y. Han, H. I. Kim Department of Chemistry Korea University Seoul 02841 (Republic of Korea) E-mail: hughkim@korea.ac.kr J. Lee, B. C. Jung, M. J. Lee Department of Biomedical Sciences Neuroscience Research Institute Seoul National University College of Medicine Seoul 03080 (Republic of Korea) E-mail: minjlee@snu.ac.kr P. Wongkongkathep, J. A. Loo Department of Chemistry and Biochemistry University of California-Los Angeles Los Angeles, CA 90095 (USA) P. Wongkongkathep Systems Biology Center, Research Affairs, Faculty of Medicine Chulalongkorn University Bangkok 10330 (Thailand) J. A. Loo Department of Biological Chemistry, David Geffen School of Medicine, University of California-Los Angeles Los Angeles, CA 90095 (USA) and UCLA Molecular Biology Institute, and UCLA/DOE Institute for Genomics and Proteomics, University of California-Los Angeles Los Angeles, CA 90095 (USA) Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/anie.201712286. Funding Information: This work was supported by the NRF of Korea (NRF) [2016R1A2B4013089 and 20100020209 (to H.I.K.), and 2016R1A2B2006507 and 2016M3C7A1913895 (to M.J.L.)], the Korea University Future Research Grant, the US NIH (R01GM103479 and S10RR028893 to J.A.L.), the US DOE (DE-FC02-02ER63421 to J.A.L.), and the Thai DPST Talents Project (to P.W.). The authors acknowledge Agilent Technologies Inc. for their support with the 6560 LC-IMS QTOFMS instrument. The synchrotron X-ray scattering measurements at the 4C SAXS II, beamline of the Pohang Accelerator Laboratory were supported by the MEST of Korea. This work was also supported by the KISTI (KSC-2016-C2-0021) and the MSIP (CAP-15-10-KRICT to H.I.K.). Publisher Copyright: {\textcopyright} 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim",
year = "2018",
month = mar,
day = "12",
doi = "10.1002/anie.201712286",
language = "English",
volume = "57",
pages = "3099--3103",
journal = "Angewandte Chemie - International Edition",
issn = "1433-7851",
publisher = "John Wiley and Sons Ltd",
number = "12",
}