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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 ?-synuclein. Previous studies have suggested that DA can interact with ?-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 ?-synuclein, and the role in progressive degeneration of DA neurons remains elusive. We have shown that in the presence of DA, recombinant human ?-synuclein produces non-fibrillar, SDS-resistant oligomers, while ?-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 ?-synuclein oligomerization in intracellular vesicles, but not in the cytosol. Furthermore, elevation of DA levels increased secretion of ?-synuclein oligomers to the extracellular space, but the secretion of monomers was not changed. DA-induced secretion of ?-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.


PROVIDER: S-EPMC3085740 | BioStudies | 2011-01-01

REPOSITORIES: biostudies

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