Exp Mol Med.  2011 Apr;43(4):216-222. 10.3858/emm.2011.43.4.026.

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

• Lee HJ
• Baek SM
• Ho DH
• Suk JE
• Cho ED
• Lee SJ

• KMID: 1104391
• DOI: http://doi.org/10.3858/emm.2011.43.4.026

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 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.

Keyword

alpha-synuclein; amyloid; dopamine; Parkinson's disease; protein aggregation; secretion

MeSH Terms

Blotting, Western
Cell Line, Tumor
Dopamine/*metabolism
Humans
Levodopa/pharmacology
Neurons/*metabolism/pathology/*secretion
Parkinson Disease/metabolism/pathology
Substantia Nigra/metabolism/pathology
alpha-Synuclein/*biosynthesis/*secretion