Journal
PLOS ONE
Volume 4, Issue 9, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0006906
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Funding
- NINDS NIH HHS [P50 NS038372, R01 NS063963, 5P50-NS38372A-06] Funding Source: Medline
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Background: Oligomerization and aggregation of alpha-synuclein molecules play a major role in neuronal dysfunction and loss in Parkinson's disease [1]. However, alpha-synuclein oligomerization and aggregation have mostly been detected indirectly in cells using detergent extraction methods [2,3,4]. A number of in vitro studies showed that dopamine can modulate the aggregation of alpha-synuclein by inhibiting the formation of or by disaggregating amyloid fibrils [5,6,7]. Methodology/Principal Findings: Here, we show that alpha-synuclein adopts a variety of conformations in primary neuronal cultures using fluorescence lifetime imaging microscopy (FLIM). Importantly, we found that dopamine, but not dopamine agonists, induced conformational changes in alpha-synuclein which could be prevented by blocking dopamine transport into the cell. Dopamine also induced conformational changes in alpha-synuclein expressed in neuronal cell lines, and these changes were also associated with alterations in oligomeric/aggregated species. Conclusion/Significance: Our results show, for the first time, a direct effect of dopamine on the conformation of alpha-synuclein in neurons, which may help explain the increased vulnerability of dopaminergic neurons in Parkinson's disease.
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