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The Journal of Neuroscience, June 22, 2005, 25(25):6016-6024; doi:10.1523/JNEUROSCI.0692-05.2005

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Neurobiology of Disease
Intravesicular Localization and Exocytosis of -Synuclein and its Aggregates

He-Jin Lee, Smita Patel, and Seung-Jae Lee

The Parkinson's Institute, Sunnyvale, California 94089

-Synuclein (-syn), particularly in its aggregated forms, is implicated in the pathogenesis of Parkinson's disease and other related neurological disorders. However, the normal biology of -syn and how it relates to the aggregation of the protein are not clearly understood. Because of the lack of the signal sequence and its predominant localization in the cytosol, -syn is generally considered exclusively an intracellular protein. Contrary to this assumption, here, we show that a small percentage of newly synthesized -syn is rapidly secreted from cells via unconventional, endoplasmic reticulum/Golgi-independent exocytosis. Consistent with this finding, we also demonstrate that a portion of cellular -syn is present in the lumen of vesicles. Importantly, the intravesicular -syn is more prone to aggregation than the cytosolic protein, and aggregated forms of -syn are also secreted from cells. Furthermore, secretion of both monomeric and aggregated -syn is elevated in response to proteasomal and mitochondrial dysfunction, cellular defects that are associated with Parkinson's pathogenesis. Thus, intravesicular localization and secretion are part of normal life cycle of -syn and might also contribute to pathological function of this protein.

Key words: synuclein; Parkinson's disease; exocytosis; protein aggregation; vesicle; neurodegeneration

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Received Feb 20, 2005; revised May 19, 2005; accepted May 22, 2005.

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