Dopamine-Induced Conformational Changes in Alpha-Synuclein
Outeiro, Tiago F.
Oliveira, Luis M. A.
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CitationOuteiro, Tiago F., Jochen Klucken, Kathryn Bercury, Julie Tetzlaff, Preeti Putcha, Luis M. A. Oliveira, Alexandre Quintas, Pamela J. McLean, and Bradley T. Hyman. 2009. Dopamine-Induced conformational changes in alpha-synuclein. PLoS ONE 4(9): e6906.
AbstractBackground: Oligomerization and aggregation of α-synuclein molecules play a major role in neuronal dysfunction and loss in Parkinson's disease . However, α-synuclein oligomerization and aggregation have mostly been detected indirectly in cells using detergent extraction methods , , . A number of in vitro studies showed that dopamine can modulate the aggregation of α-synuclein by inhibiting the formation of or by disaggregating amyloid fibrils , , . Methodology/Principal Findings: Here, we show that α-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 α-synuclein which could be prevented by blocking dopamine transport into the cell. Dopamine also induced conformational changes in α-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 α-synuclein in neurons, which may help explain the increased vulnerability of dopaminergic neurons in Parkinson's disease.
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