title: Dopamine and Cu+/2+ can induce oligomerization of α-synuclein in the absence of oxygen: Two types of oligomerization mechanisms for α-synuclein and related cell toxicity studies.
abstract: α-Synuclein oligomers can induce neurotoxicity and are implicated in Parkinson's disease etiology and disease progression. Many studies have reported α-synuclein oligomerization by dopamine (DA) and transition metal ions, but few studies provide insight into joint influences of DA and Cu2+ . In this study, DA and Cu2+ were coadministered aerobically to measure α-synuclein oligomerization under these conditions. In the presence of oxygen, DA induced α-synuclein oligomerization in a dose-dependent manner. Cu+/2+ did not effect oligomerization in such a manner in the presence of DA. By electrophoresis, Cu2+ was found easily to induce oligomerization with DA. This implies that oligomerization invoked by DA is reversible in the presence of Cu2+, which appears to be mediated by noncovalent bond interactions. In the absence of oxygen, DA induced less oligomerization of α-synuclein, whereas DA/Cu2+ induced aerobic-level amounts of oligomers, suggesting that DA/Cu2+ induces oligomerization independent of oxygen concentration. Radical species were detected through electron paramagnetic resonance (EPR) spectroscopic analysis arising from coincubation of DA/Cu2+ with α-synuclein. Redox reactions induced by DA/Cu2+ were observed in multimer regions of α-synuclein oligomers through NBT assay. Cellular toxicity results confirm that, for normal and hypoxic conditions, copper or DA/Cu2+ can induce cell death, which may arise from copper redox chemistry. From these results, we propose that DA and DA/Cu2+ induce different mechanisms of α-synuclein oligomerization, cross-linking with noncovalent (or reversible covalent) bonding vs. likely radical-mediated covalent modification.
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea; Convergence Science and Technology Research Center (CSTRC), Jungwon University, Chungbuk, Republic of Korea.
authors.forename: Yonghwang
authors.initials: Y
authors.lastname: Ha
authors.forename: Aerin
authors.initials: A
authors.lastname: Yang
authors.forename: Seyoung
authors.initials: S
authors.lastname: Lee
authors.forename: Kibong
authors.initials: K
authors.lastname: Kim
authors.forename: Hyunjeong
authors.initials: H
authors.lastname: Liew
authors.forename: Sang Hyung
authors.initials: SH
authors.lastname: Lee
authors.forename: Ju Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Hong-In
authors.initials: HI
authors.lastname: Lee
authors.forename: Yoo-Hun
authors.initials: YH
authors.lastname: Suh
authors.forename: Hee-Sung
authors.initials: HS
authors.lastname: Park
authors.forename: David G
authors.initials: DG
authors.lastname: Churchill
mesh_terms: D045744:Cell Line, Tumor; D003300:Copper / Q000494:pharmacology*; D004298:Dopamine / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D013058:Mass Spectrometry; D009447:Neuroblastoma / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051844:alpha-Synuclein / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D051844:alpha-Synuclein; D003300:Copper; D004298:Dopamine
keywords: copper; dopamine; protein cross-linking; radical-mediated chemistry; α-synuclein