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

doi:10.1126/science.1093891

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Originally published in Science Express on 22 April 2004
Science 28 May 2004:
Vol. 304. no. 5675, pp. 1328 - 1331
DOI: 10.1126/science.1093891

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

Kenny K. K. Chung,¹^,2 Bobby Thomas,¹^,2 Xiaojie Li,¹^,2 Olga Pletnikova,³ Juan C. Troncoso,²^,3 Laura Marsh,²^,4 Valina L. Dawson,¹^,2^,5^,6 Ted M. Dawson¹^,2^,5^*

Parkin is an E3 ubiquitin ligase involved in the ubiquitinationof proteins that are important in the survival of dopamine neuronsin Parkinson's disease (PD). We show that parkin is S-nitrosylatedin vitro, as well as in vivo in a mouse model of PD and in brainsof patients with PD and diffuse Lewy body disease. Moreover,S-nitrosylation inhibits parkin's ubiquitin E3 ligase activityand its protective function. The inhibition of parkin's ubiquitinE3 ligase activity by S-nitrosylation could contribute to thedegenerative process in these disorders by impairing the ubiquitinationof parkin substrates.

¹ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

^* To whom correspondence should be addressed. E-mail: tdawson{at}jhmi.edu

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TECHNICAL COMMENTS Comment on "S-Nitrosylation of Parkin Regulates Ubiquitination and Compromises Parkin's Protective Function": Stuart A. Lipton, Tomohiro Nakamura, Dongdong Yao, Zhong-Qing Shi, Takashi Uehara, and Zezong Gu (24 June 2005)
Science 308 (5730), 1870b. [DOI: 10.1126/science.1110135]
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TECHNICAL COMMENTS Response to Comment on "S-Nitrosylation of Parkin Regulates Ubiquitination and Compromises Parkin's Protective Function": Kenny K. K. Chung, Valina L. Dawson, and Ted M. Dawson (24 June 2005)
Science 308 (5730), 1870c. [DOI: 10.1126/science.1110353]
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LETTERS NO Parkin in Parkinson's Disease: Jack R. Lancaster, Jr.;, Kenny K. K. Chung, Valina L. Dawson, and Ted M. Dawson (25 June 2004)
Science 304 (5679), 1905a. [DOI: 10.1126/science.304.5679.1905a]
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