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Human Molecular Genetics Advance Access originally published online on August 12, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 20 2587-2597
DOI: 10.1093/hmg/ddg269
© 2003 Oxford University Press

The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI

Duong P. Huynh1,2, Daniel R. Scoles1,2, Dung Nguyen1 and Stefan M. Pulst1,2,3,*

1Rose Moss Laboratory for Neurogenetics, Parkinson's and Related Diseases, Burns and Allen Research Institute, Los Angeles, CA, USA, 2Division of Neurology, 8700 Beverly Blvd, Davis 2094E, Cedars-Sinai Medical Center, Los Angeles, CA, USA and 3Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA

Received May 14, 2003; Accepted August 1, 2003

Inactivating mutations of the gene encoding parkin are responsible for some forms of autosomal recessive juvenile Parkinson disease. Parkin is a ubiquitin ligase that ubiquitinates misfolded proteins targeted for the proteasome-dependent protein degradation pathway. Using the yeast two-hybrid system and co-immunoprecipitation methods, we identified synaptotagmin XI as a protein that interacts with parkin. Parkin binds to the C2A and C2B domains of synaptotagmin XI resulting in the polyubiquitination of synaptotagmin XI. Truncated and missense mutated parkins reduce parkin-sytXI binding affinity and ubiquitination. Parkin-mediated ubiquitination also enhances the turnover of sytXI. In sporadic PD brain sections, sytXI was found in the core of the Lewy bodies. Since synaptotagmin XI is a member of the synaptotagmin family that is well characterized in their importance for vesicle formation and docking, the interaction with this protein suggests a role for parkin in the regulation of the synaptic vesicle pool and in vesicle release. Loss of parkin could thus affect multiple proteins controlling vesicle pools, docking and release and explain the deficits in dopaminergic function seen in patients with parkin mutations.

* To whom correspondence should be addressed at: 8700 Beverly Blvd, Davis Research Blvd, Room 2091, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Tel: +1 3104235166; Fax: +1 8108212407; Email: pulst{at}cshs.org


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