Dopamine promotes formation and secretion of non-fibrillar alpha-synuclein oligomers

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 ${\alpha}$-synuclein. Previous studies have suggested that DA can interact with ${\alpha}$-synuclein...

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Published in:Experimental & molecular medicine 2011, Vol.43 (4), p.216-222
Main Authors: Lee, He-Jin, Baek, Sung-Min, Ho, Dong-Hwan, Suk, Ji-Eun, Cho, Eun-Duk, Lee, Seung-Jae
Format: Article
Language:Korean
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Summary: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 ${\alpha}$-synuclein. Previous studies have suggested that DA can interact with ${\alpha}$-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 ${\alpha}$-synuclein, and the role in progressive degeneration of DA neurons remains elusive. We have shown that in the presence of DA, recombinant human ${\alpha}$-synuclein produces non-fibrillar, SDS-resistant oligomers, while ${\beta}$-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 ${\alpha}$-synuclein oligomerization in intracellular vesicles, but not in the cytosol. Furthermore, elevation of DA levels increased secretion of ${\alpha}$-synuclein oligomers to the extracellular space, but the secretion of monomers was not changed. DA-induced secretion of ${\alpha}$-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.
ISSN:1226-3613
2092-6413