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Dopamine-induced conformational changes in alpha-synuclein. PLoS One 2009 Sep 04;4(9):e6906

Date

09/05/2009

Pubmed ID

19730729

Pubmed Central ID

PMC2731858

DOI

10.1371/journal.pone.0006906

Abstract

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.

Author List

Outeiro TF, Klucken J, Bercury K, Tetzlaff J, Putcha P, Oliveira LM, Quintas A, McLean PJ, Hyman BT

Author

Julie Tetzlaff PhD Associate Dean, Associate Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Line, Tumor
Cells, Cultured
Circular Dichroism
Dopamine
Humans
Mice
Microscopy, Fluorescence
Neurons
Parkinson Disease
Protein Conformation
Protein Structure, Secondary
Rats
Rats, Sprague-Dawley
alpha-Synuclein
jenkins-FCD Prod-411 e00897e83867fcfa48419861683711f8d99adb75