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J. Biol. Chem., Vol. 283, Issue 16, 10992-11003, April 18, 2008

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Single Particle Characterization of Iron-induced Pore-forming -Synuclein Oligomers^*

Marcus Kostka¹², Tobias Högen¹, Karin M. Danzer¹, Johannes Levin^¶, Matthias Habeck, Andreas Wirth^||, Richard Wagner^**, Charles G. Glabe, Sabine Finger, Udo Heinzelmann, Patrick Garidel, Wenzhen Duan, Christopher A. Ross, Hans Kretzschmar, and Armin Giese³

From the CNS Research, Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Research, Birkendorferstrasse 65, 88397 Biberach, Germany, Zentrum für Neuropathologie und Prionforschung, Ludwig-Maximilians-Universität München, Feodor Lynen-Strasse 23, 81377 München, Germany, ^¶Neurologische Klinik, Klinikum Grosshadern, Ludwig-Maximilians-Universität München, 81377 München, Germany, ^||Ionovation GmbH, 49084 Osnabrück, Germany, ^**Department of Biophysics, University of Osnabrück, 49078 Osnabrück, Germany, Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697, and the Division of Neurobiology, Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

Aggregation of -synuclein is a key event in several neurodegenerative diseases, including Parkinson disease. Recent findings suggest that oligomers represent the principal toxic aggregate species. Using confocal single-molecule fluorescence techniques, such as scanning for intensely fluorescent targets (SIFT) and atomic force microscopy, we monitored -synuclein oligomer formation at the single particle level. Organic solvents were used to trigger aggregation, which resulted in small oligomers ("intermediate I"). Under these conditions, Fe³⁺ at low micromolar concentrations dramatically increased aggregation and induced formation of larger oligomers ("intermediate II"). Both oligomer species were on-pathway to amyloid fibrils and could seed amyloid formation. Notably, only Fe³⁺-induced oligomers were SDS-resistant and could form ion-permeable pores in a planar lipid bilayer, which were inhibited by the oligomer-specific A11 antibody. Moreover, baicalein and N'-benzylidene-benzohydrazide derivatives inhibited oligomer formation. Baicalein also inhibited -synuclein-dependent toxicity in neuronal cells. Our results may provide a potential disease mechanism regarding the role of ferric iron and of toxic oligomer species in Parkinson diseases. Moreover, scanning for intensely fluorescent targets allows high throughput screening for aggregation inhibitors and may provide new approaches for drug development and therapy.

Received for publication, November 27, 2007 , and in revised form, February 5, 2008.

^* This work was supported by Deutsche Forschungsgemeinschaft Special Program Grant SFB596-B13 (to H. K. and A. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2 and Figs. S1-S6.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 49-7351-54-5415; Fax: 49-7351-54-98928; E-mail: Marcus.Kostka{at}boehringer-ingelheim.com.

³ To whom correspondence may be addressed. Tel.: 49-89-2180-78048; Fax: 49-89-2180-78037; E-mail: Armin.Giese{at}med.uni-muenchen.de.

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