title: Cu(II) promotes amyloid pore formation.
abstract: The aggregation of α-synuclein is associated with dopamine neuron death in Parkinson's disease. There is controversy in the field over the question of which species of the aggregates, fibrils or protofibrils, are toxic. Moreover, compelling evidence suggested the exposure to heavy metals to be a risk of PD. Nevertheless, the mechanism of metal ions in promoting PD remains unclear. In this research, we investigated the structural basis of Cu(II) induced aggregation of α-synuclein. Using transmission electron microscopy experiments, Cu(II) was found to promote in vitro aggregation of α-synuclein by facilitating annular protofibril formation rather than fibril formation. Furthermore, neuroprotective baicalein disaggregated annular protofibrils accompanied by considerable decrease of β-sheet content. These results strongly support the hypothesis that annular protofibrils are the toxic species, rather than fibrils, thereby inspiring us to search novel therapeutic strategies for the suppression of the toxic annular protofibril formation.
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, United States. Electronic address: hangyuz@uw.edu.
authors.forename: Hangyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, United States.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Rochet
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, United States; School of Materials Engineering, Purdue University, West Lafayette, IN 47907, United States.
authors.forename: Lia A
authors.initials: LA
authors.lastname: Stanciu
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure; D052160:Benzothiazoles; D002413:Cations, Divalent; D003300:Copper / Q000737:chemistry*; D044950:Flavanones / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D010084:Oxidation-Reduction; D066329:Protein Aggregates; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D013844:Thiazoles; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D002413:Cations, Divalent; D044950:Flavanones; D066329:Protein Aggregates; D011994:Recombinant Proteins; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T; C006680:baicalein; D003300:Copper
keywords: Amyloid; Heavy metal; Parkinson's disease; Protofibril; α-synuclein