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The Journal of Neuroscience, September 6, 2006, 26(36):9304-9311; doi:10.1523/JNEUROSCI.0519-06.2006

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Neurobiology of Disease
-Synuclein Overexpression Increases Cytosolic Catecholamine Concentration

Eugene V. Mosharov,¹ Roland G. W. Staal,¹ Jordi Bové,¹ Delphine Prou,¹ Anthonia Hananiya,¹ Dmitriy Markov,¹ Nathan Poulsen,¹ Kristin E. Larsen,¹ Candace M. H. Moore,¹ Matthew D. Troyer,⁶ Robert H. Edwards,⁶ Serge Przedborski,^1,3,4 and David Sulzer^1,2,5

Departments of ¹Neurology, ²Psychiatry, and ³Pathology and Cell Biology, and ⁴Center for Neurobiology and Behavior, Columbia University Medical Center, New York, New York 10032, ⁵Department of Neuroscience, New York Psychiatric Institute, New York, New York 10032, and ⁶Departments of Neurology and Physiology, University of California School of Medicine, San Francisco, San Francisco, California 94143

Correspondence should be addressed to David Sulzer, Black Building, Room 308, 650 West 168th Street, New York, NY 10032. Email: ds43{at}columbia.edu

Dysregulation of dopamine homeostasis and elevation of the cytosolic level of the transmitter have been suggested to underlie the vulnerability of catecholaminergic neurons in Parkinson’s disease. Because several known mutations in -synuclein or overexpression of the wild-type (WT) protein causes familial forms of Parkinson’s disease, we investigated possible links between -synuclein pathogenesis and dopamine homeostasis. Chromaffin cells isolated from transgenic mice that overexpress A30P -synuclein displayed significantly increased cytosolic catecholamine levels as measured by intracellular patch electrochemistry, whereas cells overexpressing the WT protein and those from knock-out animals were not different from controls. Likewise, catechol concentrations were higher in L-DOPA-treated PC12 cells overexpressing A30P or A53T compared with those expressing WT -synuclein, although the ability of cells to maintain a low cytosolic dopamine level after L-DOPA challenge was markedly inhibited by either protein. We also found that incubation with low-micromolar concentrations of WT, A30P, or A53T -synuclein inhibited ATP-dependent maintenance of pH gradients in isolated chromaffin vesicles and that the WT protein was significantly less potent in inducing the proton leakage. In summary, we demonstrate that overexpression of different types of -synuclein disrupts vesicular pH and leads to a marked increase in the levels of cytosolic catechol species, an effect that may in turn trigger cellular oxyradical damage. Although multiple molecular mechanisms may be responsible for the perturbation of cytosolic catecholamine homeostasis, this study provides critical evidence about how -synuclein might exert its cytotoxicity and selectively damage catecholaminergic cells.

Key words: synuclein; cytosol; catecholamine; IPE; PC12; chromaffin cell; vesicular pH

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Received Feb. 3, 2006; revised June 30, 2006; accepted July 28, 2006.

Correspondence should be addressed to David Sulzer, Black Building, Room 308, 650 West 168th Street, New York, NY 10032. Email: ds43{at}columbia.edu

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