Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

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.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Identification of a Novel Zn2+-binding Domain in the Autosomal Recessive Juvenile Parkinson-related E3 Ligase Parkin.
V. A. Hristova, S. A. Beasley, R. J. Rylett, and G. S. Shaw (2009)
J. Biol. Chem. 284, 14978-14986
   Abstract »    Full Text »    PDF »
The F-box Protein {beta}-TrCp1/Fbw1a Interacts with p300 to Enhance {beta}-Catenin Transcriptional Activity.
E. A. Kimbrel and A. L. Kung (2009)
J. Biol. Chem. 284, 13033-13044
   Abstract »    Full Text »    PDF »
Signaling by Gasotransmitters.
A. K. Mustafa, M. M. Gadalla, and S. H. Snyder (2009)
Science Signaling 2, re2
   Abstract »    Full Text »    PDF »
S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease.
A. H. K. Tsang, Y.-I. Lee, H. S. Ko, J. M. Savitt, O. Pletnikova, J. C. Troncoso, V. L. Dawson, T. M. Dawson, and K. K. K. Chung (2009)
PNAS 106, 4900-4905
   Abstract »    Full Text »    PDF »
Combined kinase inhibition modulates parkin inactivation.
E. Rubio de la Torre, B. Luzon-Toro, I. Forte-Lago, A. Minguez-Castellanos, I. Ferrer, and S. Hilfiker (2009)
Hum. Mol. Genet. 18, 809-823
   Abstract »    Full Text »    PDF »
Depletion of the ATPase NSF from Golgi membranes with hypo-S-nitrosylation of vasorelevant proteins in endothelial cells exposed to monocrotaline pyrrole.
S. Mukhopadhyay, J. Lee, and P. B. Sehgal (2008)
Am J Physiol Heart Circ Physiol 295, H1943-H1955
   Abstract »    Full Text »    PDF »
Aberrant Folding of Pathogenic Parkin Mutants: AGGREGATION VERSUS DEGRADATION.
J. S. Schlehe, A. K. Lutz, A. Pilsl, K. Lammermann, K. Grgur, I. H. Henn, J. Tatzelt, and K. F. Winklhofer (2008)
J. Biol. Chem. 283, 13771-13779
   Abstract »    Full Text »    PDF »
S-nitrosylation of peroxiredoxin 2 promotes oxidative stress-induced neuronal cell death in Parkinson's disease.
J. Fang, T. Nakamura, D.-H. Cho, Z. Gu, and S. A. Lipton (2007)
PNAS 104, 18742-18747
   Abstract »    Full Text »    PDF »
Parkinson's disease.
B. Thomas and M. F. Beal (2007)
Hum. Mol. Genet. 16, R183-R194
   Abstract »    Full Text »    PDF »
A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases.
W. Mandemakers, V. A. Morais, and B. De Strooper (2007)
J. Cell Sci. 120, 1707-1716
   Abstract »    Full Text »    PDF »
Assessment and Application of the Biotin Switch Technique for Examining Protein S-Nitrosylation under Conditions of Pharmacologically Induced Oxidative Stress.
M. T. Forrester, M. W. Foster, and J. S. Stamler (2007)
J. Biol. Chem. 282, 13977-13983
   Abstract »    Full Text »    PDF »
Mitochondrial nitric oxide in the signaling of cell integrated responses.
M. C. Carreras and J. J. Poderoso (2007)
Am J Physiol Cell Physiol 292, C1569-C1580
   Abstract »    Full Text »    PDF »
Phosphorylation of Parkin by the Cyclin-dependent Kinase 5 at the Linker Region Modulates Its Ubiquitin-Ligase Activity and Aggregation.
E. Avraham, R. Rott, E. Liani, R. Szargel, and S. Engelender (2007)
J. Biol. Chem. 282, 12842-12850
   Abstract »    Full Text »    PDF »
Biphasic Coupling of Neuronal Nitric Oxide Synthase Phosphorylation to the NMDA Receptor Regulates AMPA Receptor Trafficking and Neuronal Cell Death.
G. A. Rameau, D. S. Tukey, E. D. Garcin-Hosfield, R. F. Titcombe, C. Misra, L. Khatri, E. D. Getzoff, and E. B. Ziff (2007)
J. Neurosci. 27, 3445-3455
   Abstract »    Full Text »    PDF »
Emerging Roles for Ubiquitin and Protein Degradation in Neuronal Function.
J. J. Yi and M. D. Ehlers (2007)
Pharmacol. Rev. 59, 14-39
   Abstract »    Full Text »    PDF »
From the Cover: Structure of the Parkin in-between-ring domain provides insights for E3-ligase dysfunction in autosomal recessive Parkinson's disease.
S. A. Beasley, V. A. Hristova, and G. S. Shaw (2007)
PNAS 104, 3095-3100
   Abstract »    Full Text »    PDF »
A Classification Scheme for Redox-Based Modifications of Proteins.
M. T. Forrester and J. S. Stamler (2007)
Am. J. Respir. Cell Mol. Biol. 36, 135-137
   Full Text »    PDF »
A Drosophila Model of Mutant Human Parkin-Induced Toxicity Demonstrates Selective Loss of Dopaminergic Neurons and Dependence on Cellular Dopamine.
T.-K. Sang, H.-Y. Chang, G. M. Lawless, A. Ratnaparkhi, L. Mee, L. C. Ackerson, N. T. Maidment, D. E. Krantz, and G. R. Jackson (2007)
J. Neurosci. 27, 981-992
   Abstract »    Full Text »    PDF »
S-Nitrosylation of Bcl-2 Inhibits Its Ubiquitin-Proteasomal Degradation: A NOVEL ANTIAPOPTOTIC MECHANISM THAT SUPPRESSES APOPTOSIS.
N. Azad, V. Vallyathan, L. Wang, V. Tantishaiyakul, C. Stehlik, S. S. Leonard, and Y. Rojanasakul (2006)
J. Biol. Chem. 281, 34124-34134
   Abstract »    Full Text »    PDF »
Identification of Far Upstream Element-binding Protein-1 as an Authentic Parkin Substrate.
H. S. Ko, S. W. Kim, S. R. Sriram, V. L. Dawson, and T. M. Dawson (2006)
J. Biol. Chem. 281, 16193-16196
   Abstract »    Full Text »    PDF »
Metabolism of 3-nitrotyrosine induces apoptotic death in dopaminergic cells..
B. Blanchard-Fillion, D. Prou, M. Polydoro, D. Spielberg, E. Tsika, Z. Wang, S. L. Hazen, M. Koval, S. Przedborski, and H. Ischiropoulos (2006)
J. Neurosci. 26, 6124-6130
   Abstract »    Full Text »    PDF »
Etiology of Parkinson's disease.
A. H.V. Schapira (2006)
Neurology 66, S10-S23
   Abstract »    Full Text »
The pathogenesis of cell death in Parkinson's disease.
P. Jenner and C. W. Olanow (2006)
Neurology 66, S24-S36
   Abstract »    Full Text »
Neuroprotection by transgenic expression of glucose-6-phosphate dehydrogenase in dopaminergic nigrostriatal neurons of mice..
R. Mejias, J. Villadiego, C. O. Pintado, P. J. Vime, L. Gao, J. J. Toledo-Aral, M. Echevarria, and J. Lopez-Barneo (2006)
J. Neurosci. 26, 4500-4508
   Abstract »    Full Text »    PDF »
Inclusion body formation and neurodegeneration are parkin independent in a mouse model of alpha-synucleinopathy..
R. von Coelln, B. Thomas, S. A. Andrabi, K. L. Lim, J. M. Savitt, R. Saffary, W. Stirling, K. Bruno, E. J. Hess, M. K. Lee, et al. (2006)
J. Neurosci. 26, 3685-3696
   Abstract »    Full Text »    PDF »
Sodium Nitroprusside Promotes IRP2 Degradation via an Increase in Intracellular Iron and in the Absence of S Nitrosylation at C178..
J. Wang, C. Fillebeen, G. Chen, B. Andriopoulos, and K. Pantopoulos (2006)
Mol. Cell. Biol. 26, 1948-1954
   Abstract »    Full Text »    PDF »
S-nitrosothiol depletion in amyotrophic lateral sclerosis.
C. M. Schonhoff, M. Matsuoka, H. Tummala, M. A. Johnson, A. G. Estevéz, R. Wu, A.és Kamaid, K. C. Ricart, Y. Hashimoto, B. Gaston, et al. (2006)
PNAS 103, 2404-2409
   Abstract »    Full Text »    PDF »
Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration.
W. W. Smith, Z. Pei, H. Jiang, D. J. Moore, Y. Liang, A. B. West, V. L. Dawson, T. M. Dawson, and C. A. Ross (2005)
PNAS 102, 18676-18681
   Abstract »    Full Text »    PDF »
Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's protective function.
C. Wang, H. S. Ko, B. Thomas, F. Tsang, K. C.M. Chew, S.-P. Tay, M. W.L. Ho, T.-M. Lim, T.-W. Soong, O. Pletnikova, et al. (2005)
Hum. Mol. Genet. 14, 3885-3897
   Abstract »    Full Text »    PDF »
Nitric Oxide Regulates Transforming Growth Factor-{beta} Signaling in Endothelial Cells.
M. Saura, C. Zaragoza, B. Herranz, M. Griera, L. Diez-Marques, D. Rodriguez-Puyol, and M. Rodriguez-Puyol (2005)
Circ. Res. 97, 1115-1123
   Abstract »    Full Text »    PDF »
Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase.
C. Nathan, N. Calingasan, J. Nezezon, A. Ding, M. S. Lucia, K. La Perle, M. Fuortes, M. Lin, S. Ehrt, N. S. Kwon, et al. (2005)
J. Exp. Med. 202, 1163-1169
   Abstract »    Full Text »    PDF »
Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin.
S. R. Sriram, X. Li, H. S. Ko, K. K.K. Chung, E. Wong, K. L. Lim, V. L. Dawson, and T. M. Dawson (2005)
Hum. Mol. Genet. 14, 2571-2586
   Abstract »    Full Text »    PDF »
Accumulation of the Authentic Parkin Substrate Aminoacyl-tRNA Synthetase Cofactor, p38/JTV-1, Leads to Catecholaminergic Cell Death.
H. S. Ko, R. von Coelln, S. R. Sriram, S. W. Kim, K. K. K. Chung, O. Pletnikova, J. Troncoso, B. Johnson, R. Saffary, E. L. Goh, et al. (2005)
J. Neurosci. 25, 7968-7978
   Abstract »    Full Text »    PDF »
Avicinylation (thioesterification): A protein modification that can regulate the response to oxidative and nitrosative stress.
V. Haridas, S.-O. Kim, G. Nishimura, A. Hausladen, J. S. Stamler, and J. U. Gutterman (2005)
PNAS 102, 10088-10093
   Abstract »    Full Text »    PDF »
Comment on "S-Nitrosylation of Parkin Regulates Ubiquitination and Compromises Parkin's Protective Function".
S. A. Lipton, T. Nakamura, D. Yao, Z.-Q. Shi, T. Uehara, and Z. Gu (2005)
Science 308, 1870b
   Full Text »    PDF »
Response to Comment on "S-Nitrosylation of Parkin Regulates Ubiquitination and Compromises Parkin's Protective Function".
K. K. K. Chung, V. L. Dawson, and T. M. Dawson (2005)
Science 308, 1870c
   Full Text »    PDF »
Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease.
A. J. Whitworth, D. A. Theodore, J. C. Greene, H. Benes, P. D. Wes, and L. J. Pallanck (2005)
PNAS 102, 8024-8029
   Abstract »    Full Text »    PDF »
S-Nitrosation of the Insulin Receptor, Insulin Receptor Substrate 1, and Protein Kinase B/Akt: A Novel Mechanism of Insulin Resistance.
M. A. Carvalho-Filho, M. Ueno, S. M. Hirabara, A. B. Seabra, J. B.C. Carvalheira, M. G. de Oliveira, L. A. Velloso, R. Curi, and M. J.A. Saad (2005)
Diabetes 54, 959-967
   Abstract »    Full Text »    PDF »
Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis.
J. C. Greene, A. J. Whitworth, L. A. Andrews, T. J. Parker, and L. J. Pallanck (2005)
Hum. Mol. Genet. 14, 799-811
   Abstract »    Full Text »    PDF »
Parkin Mediates Nonclassical, Proteasomal-Independent Ubiquitination of Synphilin-1: Implications for Lewy Body Formation.
K. L. Lim, K. C. M. Chew, J. M. M. Tan, C. Wang, K. K. K. Chung, Y. Zhang, Y. Tanaka, W. Smith, S. Engelender, C. A. Ross, et al. (2005)
J. Neurosci. 25, 2002-2009
   Abstract »    Full Text »    PDF »
Parkin Phosphorylation and Modulation of Its E3 Ubiquitin Ligase Activity.
A. Yamamoto, A. Friedlein, Y. Imai, R. Takahashi, P. J. Kahle, and C. Haass (2005)
J. Biol. Chem. 280, 3390-3399
   Abstract »    Full Text »    PDF »
Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress.
D. J. Moore, L. Zhang, J. Troncoso, M. K. Lee, N. Hattori, Y. Mizuno, T. M. Dawson, and V. L. Dawson (2005)
Hum. Mol. Genet. 14, 71-84
   Abstract »    Full Text »    PDF »
Mitochondrial Injury: A Hot Spot for Parkinsonism and Parkinson's Disease?.
B. I. Giasson (2004)
Sci. Aging Knowl. Environ. 2004, pe42
   Abstract »    Full Text »
The Moving Frontier in Nitric Oxide-Dependent Signaling.
C. Nathan (2004)
Sci. STKE 2004, pe52
   Abstract »    Full Text »    PDF »
Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity.
D. Yao, Z. Gu, T. Nakamura, Z.-Q. Shi, Y. Ma, B. Gaston, L. A. Palmer, E. M. Rockenstein, Z. Zhang, E. Masliah, et al. (2004)
PNAS 101, 10810-10814
   Abstract »    Full Text »    PDF »
S-nitrosylation: Physiological regulation of NF-{kappa}B.
H. E. Marshall, D. T. Hess, and J. S. Stamler (2004)
PNAS 101, 8841-8842
   Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)