Dopamine-induced conformational changes in alpha-synuclein

Tiago F. Outerio, Jochen Klucken, Kathryn Bercury, Julie Tetzlaff, Preeti Putcha, Luis M.A. Oliveira, Alexandre Quintas, Pamela J. McLean, Bradley T. Hyman

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Background: 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 a-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.

Original languageEnglish (US)
Article numbere6906
JournalPloS one
Volume4
Issue number9
DOIs
StatePublished - Sep 4 2009

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Outerio, T. F., Klucken, J., Bercury, K., Tetzlaff, J., Putcha, P., Oliveira, L. M. A., Quintas, A., McLean, P. J., & Hyman, B. T. (2009). Dopamine-induced conformational changes in alpha-synuclein. PloS one, 4(9), [e6906]. https://doi.org/10.1371/journal.pone.0006906