title: Dopamine promotes formation and secretion of non-fibrillar alpha-synuclein oligomers.
abstract: Parkinson's disease (PD) is characterized by selective and progressive degeneration of dopamine (DA)-producing neurons in the substantia nigra pars compacta (SNpc) and by abnormal aggregation of α-synuclein. Previous studies have suggested that DA can interact with α-synuclein, thus modulating the aggregation process of this protein; this interaction may account for the selective vulnerability of DA neurons in patients with PD. However, the relationship between DA and α-synuclein, and the role in progressive degeneration of DA neurons remains elusive. We have shown that in the presence of DA, recombinant human α-synuclein produces non-fibrillar, SDS-resistant oligomers, while β-sheet-rich fibril formation is inhibited. Pharmacologic elevation of the cytoplasmic DA level increased the formation of SDS-resistant oligomers in DA-producing neuronal cells. DA promoted α-synuclein oligomerization in intracellular vesicles, but not in the cytosol. Furthermore, elevation of DA levels increased secretion of α-synuclein oligomers to the extracellular space, but the secretion of monomers was not changed. DA-induced secretion of α-synuclein oligomers may contribute to the progressive loss of the dopaminergic neuronal population and the pronounced neuroinflammation observed in the SNpc in patients with PD.
authors.affiliation: Department of Anatomy, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: He-Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Baek
authors.forename: Dong-Hwan
authors.initials: DH
authors.lastname: Ho
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Suk
authors.forename: Eun-Duk
authors.initials: ED
authors.lastname: Cho
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D007980:Levodopa / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D007980:Levodopa; D004298:Dopamine