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Detection of novel intracellular -synuclein oligomeric species by fluorescence lifetime imaging

Jochen Klucken^*,, Tiago F. Outeiro^*, Paul Nguyen^*, Pamela J. McLean^*,1 and Bradley T. Hyman^*

^* MassGeneral Institute for Neurodegenerative Disease, Alzheimer’s Disease Research Unit, Massachusetts General Hospital, Charlestown, Massachusetts, USA;

Department of Neurology, University of Regensburg, Regensburg, Germany

¹Correspondence: MassGeneral Institute for Neurodegenerative Disease, Alzheimer’s Disease Research Unit, Massachusetts General Hospital, 114 16^th St., Charlestown, MA 02129 USA. E-mail: pmclean{at}partners.org

Oligomerization and aggregation of -synuclein molecules are believed to play a major role in neuronal dysfunction and loss in Parkinson’s disease (PD) and dementia with Lewy bodies. However, -synuclein oligomerization and aggregation have been detected only indirectly in cells using detergent extraction methods. Here, we show for the first time intracellular -synuclein oligomerization using fluorescence lifetime imaging (FLIM). Two forms of -synuclein homomeric interactions were detected: an antiparallel amino terminus-carboxyl terminus interaction between -synuclein molecules, and a close amino terminus-carboxy terminus interaction within single -synuclein molecules. Coexpression of the chaperone protein Hsp70, which can block -synuclein toxicity in several systems, causes -synuclein to adopt a different, open conformation, but Hsp70 does not alter -synuclein–-synuclein interactions. Thus, the neuroprotective effect of Hsp70 can be explained by its chaperone activity on -synuclein molecules, rather than alteration of -synuclein–-synuclein interactions.—Klucken, J., Outeiro, T. F., Nyugen, P., McLean, P. J., and Hyman, B. T. Detection of novel intracellular -synuclein oligomeric species by fluorescence lifetime imaging.

Key Words: Parkinson’s disease • Lewy body disease • chaperone • protein aggregation

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