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The Journal of Neuroscience, November 15, 2006, 26(46):11915-11922; doi:10.1523/JNEUROSCI.3821-06.2006

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Neurobiology of Disease
-Synuclein Overexpression in PC12 and Chromaffin Cells Impairs Catecholamine Release by Interfering with a Late Step in Exocytosis

Kristin E. Larsen,^1 * Yvonne Schmitz,^1 * Matthew D. Troyer,⁵ Eugene Mosharov,¹ Paula Dietrich,¹ Abrar Z. Quazi,⁶ Magali Savalle,¹ Venu Nemani,⁵ Farrukh A. Chaudhry,⁶ Robert H. Edwards,⁵ Leonidas Stefanis,^1,2 and David Sulzer^1,3,4

Departments of ¹Neurology, ²Pathology, and ³Psychiatry and Pharmacology, Columbia University School of Medicine, New York, New York 10032, ⁴Department of Neuroscience, New York Psychiatric Institute, New York, New York 10032, ⁵Departments of Neurology and Physiology, University of California School of Medicine, San Francisco, San Francisco, California 94143, and ⁶Biotechnology Centre of Oslo and Centre for Molecular Biology and Neuroscience, University of Oslo, N-0317, Oslo, Norway

Correspondence should be addressed to Dr. David Sulzer, Black Building, Room 305, 650 West 168th Street, New York, NY 10032. Email: ds43{at}columbia.edu

-Synuclein (-syn), a protein implicated in Parkinson's disease pathogenesis, is a presynaptic protein suggested to regulate transmitter release. We explored how -syn overexpression in PC12 and chromaffin cells, which exhibit low endogenous -syn levels relative to neurons, affects catecholamine release. Overexpression of wild-type or A30P mutant -syn in PC12 cell lines inhibited evoked catecholamine release without altering calcium threshold or cooperativity of release. Electron micrographs revealed that vesicular pools were not reduced but that, on the contrary, a marked accumulation of morphologically "docked" vesicles was apparent in the -syn-overexpressing lines. We used amperometric recordings from chromaffin cells derived from mice that overexpress A30P or wild-type (WT) -syn, as well as chromaffin cells from control and -syn null mice, to determine whether the filling of vesicles with the transmitter was altered. The quantal size and shape characteristics of amperometric events were identical for all mouse lines, suggesting that overexpression of WT or mutant -syn did not affect vesicular transmitter accumulation or the kinetics of vesicle fusion. The frequency and number of exocytotic events per stimulus, however, was lower for both WT and A30P -syn-overexpressing cells. The -syn-overexpressing cells exhibited reduced depression of evoked release in response to repeated stimuli, consistent with a smaller population of readily releasable vesicles. We conclude that -syn overexpression inhibits a vesicle "priming" step, after secretory vesicle trafficking to "docking" sites but before calcium-dependent vesicle membrane fusion.

Key words: amperometry; catecholamine; chromaffin; exocytosis; Parkinson's disease; secretory

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Received March 7, 2006; accepted Sept. 29, 2006.

Correspondence should be addressed to Dr. David Sulzer, Black Building, Room 305, 650 West 168th Street, New York, NY 10032. Email: ds43{at}columbia.edu

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