121st General Meeting of the KCS

Type Oral Presentation
Area Oral Presentation for 2018 DOW Chemical Korea Award
Room No. Room 202A
Time THU 10:55-:
Code KCS.O-6
Subject Supramolecular Modulation of Structural Polymorphism in Pathogenic α-Synuclein Fibrils Using Cu(II) Coordination
Authors Tae Su Choi, Jeeyoung Lee1, Jong Yoon Han, Byung Chul Jung1, Piriya Wongkongkathep2, Joseph A. Loo2, Min Jae Lee1,*, Hugh I. Kim*
Department of Chemistry, Korea University, Korea
1Department of Biomedical Sciences, Neuroscience Research, Korea
2Department of Chemistry and Biochemistry, University of California-Los Angeles, United States
Abstract Amyloid fibrillation of α-Synuclein (αSyn) has been linked with several synucleinopathies such as Parkinson’s disease (PD), dementia with Lewy body (DLB), and multiple system atrophy (MSA). During the fibrillation, αSyn self-assemble to beta-sheet rich amyloid fibrils with diverse morphologic variations. Since the morphology of αSyn fibrils determines their cell-transmission and cytotoxicity, understanding the mechanism of morphologic variations in αSyn fibrils is crucial. In the present study, I and my coworkers suggested that Cu(II) induces non-canonical self-assembly of αSyn, thereby promoting the formation of beta-sheet rich, short αSyn fibrils. Cu(II) is abundant in substantia nigra of human brain, where the dopaminergic neurons are damaged in patients with PD. In addition, Cu(II)-induced short fibrils were highly transmissible to cell interior, causing cytotoxicity through the cell malfunctions in protein degradation. Using small-angle X-ray scattering (SAXS) and ion mobility-mass spectrometry (IM-MS), the molecular conformation of αSyn monomer-Cu(II) complex was investigated. αSyn monomer-Cu(II) formed the macrochelated complex that promotes the nucleation process of αSyn, but retards the elongation of αSyn fibrils. Our result indicates that the formation mechanism of pathological αSyn fibrils is involved in non-canonical self-assembly through Cu(II).
E-mail choitaesu@korea.ac.kr