Dopamine-induced conformational changes in alpha-synuclein.
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].


RESULTS
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.


CONCLUSIONS
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.
Outeiro
Tiago F
TF
MassGeneral Institute for Neurodegenerative Disease, Alzheimer Research Unit, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America. touteiro@fm.ul.pt
Klucken
Jochen
J
Bercury
Kathryn
K
Tetzlaff
Julie
J
Putcha
Preeti
P
Oliveira
Luis M A
LM
Quintas
Alexandre
A
McLean
Pamela J
PJ
Hyman
Bradley T
BT
D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002942:Circular Dichroism; D004298:Dopamine / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D051381:Rats; D017207:Rats, Sprague-Dawley; D051844:alpha-Synuclein / Q000737:chemistry*
D051844:alpha-Synuclein; D004298:Dopamine