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Published Online April 22, 2004
Science DOI: 10.1126/science.1093891

Reports

Submitted on November 21, 2003
Accepted on April 13, 2004

S-Nitrosylation of Parkin Regulates Ubiquitination and Compromises Parkin's Protective Function

Kenny K. K. Chung 1, Ted M. Dawson 2*, Bobby Thomas 3, Xiaojie Li 3, Olga Pletnikova 4, Juan C. Troncoso 5, Laura Marsh 6, Valina L. Dawson 7

1 Institute for Cell Engineering, Dept. of Neurobiology, Suite 731, Johns Hopkins University School of Medicine, 733 North Broadway Street, Baltimore, MD 21205, USA.
2 Institute for Cell Engineering, Departments of Neurology, Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3 Institute for Cell Engineering, Dept. of Neurology, Suite 731, Johns Hopkins University School of Medicine, 733 North Broadway Street, Baltimore, MD 21205, USA.
4 Department of Pathology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21205, USA.
5 Department of Neurology and Pathology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21205, USA.
6 Department of Neurology and Psychology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21205, USA.
7 Institute for Cell Engineering, Departments of Neurology, Neuroscience, and Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

* To whom correspondence should be addressed.
Ted M. Dawson , E-mail: tdawson{at}jhmi.edu

Parkin is an E3 ubiquitin ligase, which is involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). Here we show that parkin is S-nitrosylated in vitro, and in vivo in the MPTP animal model of PD and in brains of patients with PD and diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's ubiquitin E3-ligase activity and its protective function. The inhibition of parkin's ubiquitin E3-ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates and parkin's protective function.


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