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The Journal of Neuroscience, February 4, 2009, 29(5):1480-1485; doi:10.1523/JNEUROSCI.6202-08.2009

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Brief Communications
Rab11a and HSP90 Regulate Recycling of Extracellular -Synuclein

Jun Liu,^1,2 Jian-Peng Zhang,² Min Shi,² Thomas Quinn,² Joshua Bradner,² Richard Beyer,³ Shengdi Chen,¹ and Jing Zhang²

¹Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China, ²Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98104, and ³Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105

Correspondence should be addressed to Jing Zhang, Department of Pathology, University of Washington School of Medicine, HMC Box 359635, 325 9th Avenue, Seattle, WA 98104. Email: zhangj{at}u.washington.edu

Growing evidence suggests that extracellular -synuclein (eSNCA) may play an important role in the pathogenesis of Parkinson's disease (PD) and related synucleinopathies by producing neurotoxicity directly or via activation of glia. However, the mechanisms involved in the trafficking of eSNCA in neurons and/or glia remain unclear. Here, we demonstrated that eSNCA could be resecreted out of neurons via a process modulated by a recycling endosome regulator rab11a in addition to being degraded by an endosome–lysosome system. A quantitative proteomic analysis also revealed numerous proteins through which rab11a might execute its function. One of the candidate proteins, heat shock protein 90 (HSP90), was validated to be interacting with rab11a. Furthermore, geldanamycin, an HSP90 inhibitor, not only prevented resecretion of eSNCA but also attenuated neurotoxicity induced by eSNCA.

Key words: -synuclein; exocytosis; rab11a; HSP90; Parkinson's disease; synucleinopathy; proteomics

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Received Dec. 31, 2008; accepted Jan. 2, 2009.

Correspondence should be addressed to Jing Zhang, Department of Pathology, University of Washington School of Medicine, HMC Box 359635, 325 9th Avenue, Seattle, WA 98104. Email: zhangj{at}u.washington.edu

This article has been cited by other articles:

				S. F. Falsone, A. J. Kungl, A. Rek, R. Cappai, and K. Zangger The Molecular Chaperone Hsp90 Modulates Intermediate Steps of Amyloid Assembly of the Parkinson-related Protein {alpha}-Synuclein J. Biol. Chem., November 6, 2009; 284(45): 31190 - 31199. [Abstract] [Full Text] [PDF]

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