 |
|||||
|
|||||
|
|||||
|
|||||
|
|||||
The Journal of Neuroscience, February 23, 2005, 25(8):2002-2009; doi:10.1523/JNEUROSCI.4474-04.2005
Previous Article | Next Article
Neurobiology of Disease
Parkin Mediates Nonclassical, Proteasomal-Independent Ubiquitination of Synphilin-1: Implications for Lewy Body Formation
Kah Leong Lim,1,2,6,7 Katherine C. M. Chew,6,7 Jeanne M. M. Tan,6 Cheng Wang,6,7 Kenny K. K. Chung,1,2 Yi Zhang,1,3 Yuji Tanaka,4 Wanli Smith,4 Simone Engelender,8 Christopher A. Ross,2,3,4 Valina L. Dawson,1,2,3,5 andTed M. Dawson1,2,3 1Institute for Cell Engineering, Departments of 2Neurology and 3Neuroscience, 4Division of Neurobiology, 5Department of Psychiatry and Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, 6Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore, S308433, 7Department of Biological Sciences, National University of Singapore, Singapore, S117542, and 8Department of Pharmacology, Technion-Israel Institute of Technology, Haifa 31096, Israel
It is widely accepted that the familial Parkinson's disease (PD)-linked gene product, parkin, functions as a ubiquitin ligase involved in protein turnover via the ubiquitin-proteasome system. Substrates ubiquitinated by parkin are hence thought to be destined for proteasomal degradation. Because we demonstrated previously that parkin interacts with and ubiquitinates synphilin-1, we initially expected synphilin-1 degradation to be enhanced in the presence of parkin. Contrary to our expectation, we found that synphilin-1 is normally ubiquitinated by parkin in a nonclassical, proteasomal-independent manner that involves lysine 63 (K63)-linked polyubiquitin chain formation. Parkin-mediated degradation of synphilin-1 occurs appreciably only at an unusually high parkin to synphilin-1 expression ratio or when primed for lysine 48 (K48)-linked ubiquitination. In addition we found that parkin-mediated ubiquitination of proteins within Lewy-body-like inclusions formed by the coexpression of synphilin-1,
-synuclein, and parkin occurs predominantly via K63 linkages and that the formation of these inclusions is enhanced by K63-linked ubiquitination. Our results suggest that parkin is a dual-function ubiquitin ligase and that K63-linked ubiquitination of synphilin-1 by parkin may be involved in the formation of Lewy body inclusions associated with PD.
Key words: parkin; synphilin-1; ubiquitin; Parkinson's disease; Lewy body; dopamine
Received Oct 31, 2004; revised January 6, 2005; accepted January 6, 2005.
This article has been cited by other articles:
Y. J. Machida, Y. Machida, A. A. Vashisht, J. A. Wohlschlegel, and A. Dutta
The Deubiquitinating Enzyme BAP1 Regulates Cell Growth via Interaction with HCF-1
J. Biol. Chem., December 4, 2009; 284(49): 34179 - 34188.
[Abstract] [Full Text] [PDF]
O. Rothfuss, H. Fischer, T. Hasegawa, M. Maisel, P. Leitner, F. Miesel, M. Sharma, A. Bornemann, D. Berg, T. Gasser, et al.
Parkin protects mitochondrial genome integrity and supports mitochondrial DNA repair
Hum. Mol. Genet., October 15, 2009; 18(20): 3832 - 3850.
[Abstract] [Full Text] [PDF]
V. A. Hristova, S. A. Beasley, R. J. Rylett, and G. S. Shaw
Identification of a Novel Zn2+-binding Domain in the Autosomal Recessive Juvenile Parkinson-related E3 Ligase Parkin
J. Biol. Chem., May 29, 2009; 284(22): 14978 - 14986.
[Abstract] [Full Text] [PDF]
Y. Wang, A. B. Meriin, N. Zaarur, N. V. Romanova, Y. O. Chernoff, C. E. Costello, and M. Y. Sherman
Abnormal proteins can form aggresome in yeast: aggresome-targeting signals and components of the machinery
FASEB J, February 1, 2009; 23(2): 451 - 463.
[Abstract] [Full Text] [PDF]
N. Zaarur, A. B. Meriin, V. L. Gabai, and M. Y. Sherman
Triggering Aggresome Formation: DISSECTING AGGRESOME-TARGETING AND AGGREGATION SIGNALS IN SYNPHILIN 1
J. Biol. Chem., October 10, 2008; 283(41): 27575 - 27584.
[Abstract] [Full Text] [PDF]
E. S.P. Wong, J. M.M. Tan, W.-E Soong, K. Hussein, N. Nukina, V. L. Dawson, T. M. Dawson, A. M. Cuervo, and K.-L. Lim
Autophagy-mediated clearance of aggresomes is not a universal phenomenon
Hum. Mol. Genet., August 15, 2008; 17(16): 2570 - 2582.
[Abstract] [Full Text] [PDF]
J. M.M. Tan, E. S.P. Wong, D. S. Kirkpatrick, O. Pletnikova, H. S. Ko, S.-P. Tay, M. W.L. Ho, J. Troncoso, S. P. Gygi, M. K. Lee, et al.
Lysine 63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions associated with neurodegenerative diseases
Hum. Mol. Genet., February 1, 2008; 17(3): 431 - 439.
[Abstract] [Full Text] [PDF]
J. A. Olzmann, L. Li, M. V. Chudaev, J. Chen, F. A. Perez, R. D. Palmiter, and L.-S. Chin
Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6
J. Cell Biol., September 7, 2007; 178(6): 1025 - 1038.
[Abstract] [Full Text] [PDF]
M. Joch, A. R. Ase, C. X.-Q. Chen, P. A. MacDonald, M. Kontogiannea, A. T. Corera, A. Brice, P. Seguela, and E. A. Fon
Parkin-mediated Monoubiquitination of the PDZ Protein PICK1 Regulates the Activity of Acid-sensing Ion Channels
Mol. Biol. Cell, August 1, 2007; 18(8): 3105 - 3118.
[Abstract] [Full Text] [PDF]
F. P. Marx, A. S. Soehn, D. Berg, C. Melle, C. Schiesling, M. Lang, S. Kautzmann, K. M. Strauss, T. Franck, S. Engelender, et al.
The proteasomal subunit S6 ATPase is a novel synphilin-1 interacting protein--implications for Parkinson's disease
FASEB J, June 1, 2007; 21(8): 1759 - 1767.
[Abstract] [Full Text] [PDF]
C. Liu, E. Fei, N. Jia, H. Wang, R. Tao, A. Iwata, N. Nukina, J. Zhou, and G. Wang
Assembly of Lysine 63-linked Ubiquitin Conjugates by Phosphorylated {alpha}-Synuclein Implies Lewy Body Biogenesis
J. Biol. Chem., May 11, 2007; 282(19): 14558 - 14566.
[Abstract] [Full Text] [PDF]
E. Avraham, R. Rott, E. Liani, R. Szargel, and S. Engelender
Phosphorylation of Parkin by the Cyclin-dependent Kinase 5 at the Linker Region Modulates Its Ubiquitin-Ligase Activity and Aggregation
J. Biol. Chem., April 27, 2007; 282(17): 12842 - 12850.
[Abstract] [Full Text] [PDF]
D. L. Shattuck, J. K. Miller, M. Laederich, M. Funes, H. Petersen, K. L. Carraway III, and C. Sweeney
LRIG1 Is a Novel Negative Regulator of the Met Receptor and Opposes Met and Her2 Synergy
Mol. Cell. Biol., March 1, 2007; 27(5): 1934 - 1946.
[Abstract] [Full Text] [PDF]
D. Mukhopadhyay and H. Riezman
Proteasome-Independent Functions of Ubiquitin in Endocytosis and Signaling
Science, January 12, 2007; 315(5809): 201 - 205.
[Abstract] [Full Text] [PDF]
Y. Leng and D.-M. Chuang
Endogenous alpha-synuclein is induced by valproic acid through histone deacetylase inhibition and participates in neuroprotection against glutamate-induced excitotoxicity.
J. Neurosci., July 12, 2006; 26(28): 7502 - 7512.
[Abstract] [Full Text] [PDF]
C. Hampe, H. Ardila-Osorio, M. Fournier, A. Brice, and O. Corti
Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity
Hum. Mol. Genet., July 1, 2006; 15(13): 2059 - 2075.
[Abstract] [Full Text] [PDF]
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.
Inclusion body formation and neurodegeneration are parkin independent in a mouse model of alpha-synucleinopathy.
J. Neurosci., April 5, 2006; 26(14): 3685 - 3696.
[Abstract] [Full Text] [PDF]
A. Ryo, T. Togo, T. Nakai, A. Hirai, M. Nishi, A. Yamaguchi, K. Suzuki, Y. Hirayasu, H. Kobayashi, K. Perrem, et al.
Prolyl-isomerase Pin1 Accumulates in Lewy Bodies of Parkinson Disease and Facilitates Formation of {alpha}-Synuclein Inclusions
J. Biol. Chem., February 17, 2006; 281(7): 4117 - 4125.
[Abstract] [Full Text] [PDF]
N. Matsuda, T. Kitami, T. Suzuki, Y. Mizuno, N. Hattori, and K. Tanaka
Diverse Effects of Pathogenic Mutations of Parkin That Catalyze Multiple Monoubiquitylation in Vitro
J. Biol. Chem., February 10, 2006; 281(6): 3204 - 3209.
[Abstract] [Full Text] [PDF]
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.
Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's protective function
Hum. Mol. Genet., December 15, 2005; 14(24): 3885 - 3897.
[Abstract] [Full Text] [PDF]
J. A.F. Marteijn, L. van Emst, C. A.J. Erpelinck-Verschueren, G. Nikoloski, A. Menke, T. de Witte, B. Lowenberg, J. H. Jansen, and B. A. van der Reijden
The E3 ubiquitin-protein ligase Triad1 inhibits clonogenic growth of primary myeloid progenitor cells
Blood, December 15, 2005; 106(13): 4114 - 4123.
[Abstract] [Full Text] [PDF]
W. Springer, T. Hoppe, E. Schmidt, and R. Baumeister
A Caenorhabditis elegans Parkin mutant with altered solubility couples {alpha}-synuclein aggregation to proteotoxic stress
Hum. Mol. Genet., November 15, 2005; 14(22): 3407 - 3423.
[Abstract] [Full Text] [PDF]
S. R. Sriram, X. Li, H. S. Ko, K. K.K. Chung, E. Wong, K. L. Lim, V. L. Dawson, and T. M. Dawson
Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin
Hum. Mol. Genet., September 1, 2005; 14(17): 2571 - 2586.
[Abstract] [Full Text] [PDF]
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.
Accumulation of the Authentic Parkin Substrate Aminoacyl-tRNA Synthetase Cofactor, p38/JTV-1, Leads to Catecholaminergic Cell Death
J. Neurosci., August 31, 2005; 25(35): 7968 - 7978.
[Abstract] [Full Text] [PDF]
P. L. Andersen, H. Zhou, L. Pastushok, T. Moraes, S. McKenna, B. Ziola, M. J. Ellison, V. M. Dixit, and W. Xiao
Distinct regulation of Ubc13 functions by the two ubiquitin-conjugating enzyme variants Mms2 and Uev1A
J. Cell Biol., August 29, 2005; 170(5): 745 - 755.
[Abstract] [Full Text] [PDF]
W. W. Smith, R. L. Margolis, X. Li, J. C. Troncoso, M. K. Lee, V. L. Dawson, T. M. Dawson, T. Iwatsubo, and C. A. Ross
{alpha}-Synuclein Phosphorylation Enhances Eosinophilic Cytoplasmic Inclusion Formation in SH-SY5Y Cells
J. Neurosci., June 8, 2005; 25(23): 5544 - 5552.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|