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The Journal of Neuroscience, November 19, 2008, 28(47):12305-12317; doi:10.1523/JNEUROSCI.3088-08.2008

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Neurobiology of Disease
Optical Reporters for the Conformation of -Synuclein Reveal a Specific Interaction with Mitochondria

Ken Nakamura,¹ Venu M. Nemani,¹ Erika K. Wallender,¹ Katrin Kaehlcke,² Melanie Ott,² and Robert H. Edwards¹

¹Graduate Programs in Neuroscience and Cell Biology, Departments of Neurology and Physiology, and ²Gladstone Institute of Immunology, University of California at San Francisco, San Francisco, California 94143

Correspondence should be addressed to Robert H. Edwards, Departments of Neurology and Physiology, UCSF School of Medicine, 600 16th Street, GH-N272B, San Francisco, CA 94143. Email: robert.edwards{at}ucsf.edu

The aggregation of abnormally folded proteins is a defining feature of neurodegenerative disease, but it has not previously been possible to assess the conformation of these proteins in a physiologically relevant context, before they form morphologically recognizable aggregates. We now describe FRET-based reporters for the conformation of -synuclein, a protein central to the pathogenesis of Parkinson's disease (PD). Characterization in vitro shows that -synuclein adopts a relatively "closed" conformation in solution that converts to "open" on membrane binding. In living cells, the closed conformation predominates. In neurons, however, cell bodies contain a much larger proportion of the open conformation than synaptic boutons. To account for these differences, we also used the reporters to characterize the interaction with native membranes. We find that the conformation of -synuclein responds selectively to mitochondria, indicating a direct link between -synuclein and an organelle strongly implicated in the pathogenesis of PD.

Key words: synuclein; protein conformation; Parkinson's disease; mitochondria; neural degeneration; FRET

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Received July 2, 2008; revised Oct. 4, 2008; accepted Oct. 8, 2008.

Correspondence should be addressed to Robert H. Edwards, Departments of Neurology and Physiology, UCSF School of Medicine, 600 16th Street, GH-N272B, San Francisco, CA 94143. Email: robert.edwards{at}ucsf.edu

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