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J. Biol. Chem., Vol. 283, Issue 35, 23542-23556, August 29, 2008

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Wild Type -Synuclein Is Degraded by Chaperone-mediated Autophagy and Macroautophagy in Neuronal Cells^*

Tereza Vogiatzi¹, Maria Xilouri¹, Kostas Vekrellis, and Leonidas Stefanis²

From the Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Soranou Efesiou 4, 11527 Athens and Second Department of Neurology, Attikon Hospital, University of Athens Medical School, 124 62, Athens, Greece

-Synuclein (ASYN) is crucial in Parkinson disease (PD) pathogenesis. Increased levels of wild type (WT) ASYN expression are sufficient to cause PD in humans. The manner of post-transcriptional regulation of ASYN levels is controversial. Previously, we had shown that WT ASYN can be degraded by chaperone-mediated autophagy (CMA) in isolated liver lysosomes. Whether this occurs in a cellular and, in particular, in a neuronal cell context is unclear. Using a mutant ASYN form that lacks the CMA recognition motif and RNA interference against the rate-limiting step in the CMA pathway, Lamp2a, we show here that CMA is indeed involved in WT ASYN degradation in PC12 and SH-SY5Y cells, and in primary cortical and midbrain neurons. However, the extent of involvement varies between cell types, potentially because of differences in compensatory mechanisms. CMA inhibition leads to an accumulation of soluble high molecular weight and detergent-insoluble species of ASYN, suggesting that CMA dysfunction may play a role in the generation of such aberrant species in PD. ASYN and Lamp2a are developmentally regulated in parallel in cortical neuron cultures and in vivo in the central nervous system, and they physically interact as indicated by co-immunoprecipitation. In contrast to previous reports, inhibition of macroautophagy, but not the proteasome, also leads to WT ASYN accumulation, suggesting that this lysosomal pathway is also involved in normal ASYN turnover. These results indicate that CMA and macroautophagy are important pathways for WT ASYN degradation in neurons and underline the importance of CMA as degradation machinery in the nervous system.

Received for publication, March 12, 2008 , and in revised form, June 19, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R21 NS055693 (to L. S. and K. V.). This work was also supported by a grant from the Parkinson Disease Foundation (to K. V.). 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 Figs. 1–3.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens 4, Soranou Efesiou St., Athens 11527, Greece. Tel.: 30-210-6597214; Fax: 30-210-6597545; E-mail: lstefanis{at}bioacademy.gr.

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