Human Molecular Genetics Advance Access originally published online on November 3, 2004
Human Molecular Genetics 2005 14(1):71-84; doi:10.1093/hmg/ddi007
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Human Molecular Genetics, Vol. 14, No. 1 © Oxford University Press 2005; all rights reserved
Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress
1Institute for Cell Engineering, 2Department of Neurology, 3Department of Pathology, 4Department of Neuroscience and 5Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA and 6Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-0033, Japan
* To whom correspondence should be addressed at: Department of Neurology, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N. Broadway, Suite 731, Baltimore, MD 21205, USA. Tel: +1 4106143359; Fax: +1 4106149568; Email: vdawson{at}jhmi.edu
Received June 6, 2004; Revised August 11, 2004; Accepted October 22, 2004
The identification of rare monogenic forms of Parkinson's disease (PD) has provided tremendous insight into the molecular pathogenesis of this disorder. Heritable mutations in 
-synuclein, parkin, DJ-1 and PINK1 cause familial forms of PD. In the more common sporadic form of PD, oxidative stress and derangements in mitochondrial complex-I function are considered to play a prominent role in disease pathogenesis. However, the relationship of DJ-1 with other PD-linked genes and oxidative stress has not been explored. Here, we show that pathogenic mutant forms of DJ-1 specifically but differentially associate with parkin, an E3 ubiquitin ligase. Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1. Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells. The interaction of parkin with L166P DJ-1 may involve a larger protein complex that contains CHIP and Hsp70, perhaps accounting for the lack of parkin-mediated ubiquitination. Oxidative stress also promotes an interaction between DJ-1 and parkin, but this does not result in the ubiquitination or degradation of DJ-1. Parkin-mediated alterations in DJ-1 protein stability may be pathogenically relevant as DJ-1 levels are dramatically increased in the detergent-insoluble fraction from sporadic PD/DLB brains, but are reduced in the insoluble fraction from parkin-linked autosomal recessive juvenile-onset PD brains. These data potentially link DJ-1 and parkin in a common molecular pathway at multiple levels that may have important implications for understanding the pathogenesis of inherited and sporadic PD.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Saha, M. D. Guillily, A. Ferree, J. Lanceta, D. Chan, J. Ghosh, C. H. Hsu, L. Segal, K. Raghavan, K. Matsumoto, et al. LRRK2 Modulates Vulnerability to Mitochondrial Dysfunction in Caenorhabditis elegans J. Neurosci., July 22, 2009; 29(29): 9210 - 9218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Samann, J. Hegermann, E. von Gromoff, S. Eimer, R. Baumeister, and E. Schmidt Caenorhabditits elegans LRK-1 and PINK-1 Act Antagonistically in Stress Response and Neurite Outgrowth J. Biol. Chem., June 12, 2009; 284(24): 16482 - 16491. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-S. Cha, H. I. Jung, H. Jeon, Y. J. An, I.-K. Kim, S. Yun, H. J. Ahn, K. C. Chung, S. H. Lee, P.-G. Suh, et al. Crystal Structure of Filamentous Aggregates of Human DJ-1 Formed in an Inorganic Phosphate-dependent Manner J. Biol. Chem., December 5, 2008; 283(49): 34069 - 34075. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Mizuno, N. Hattori, S.-i. Kubo, S. Sato, K. Nishioka, T. Hatano, H. Tomiyama, M. Funayama, Y. Machida, and H. Mochizuki Progress in the pathogenesis and genetics of Parkinson's disease Phil Trans R Soc B, June 27, 2008; 363(1500): 2215 - 2227. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Devi, V. Raghavendran, B. M. Prabhu, N. G. Avadhani, and H. K. Anandatheerthavarada Mitochondrial Import and Accumulation of {alpha}-Synuclein Impair Complex I in Human Dopaminergic Neuronal Cultures and Parkinson Disease Brain J. Biol. Chem., April 4, 2008; 283(14): 9089 - 9100. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Thomas and M. F. Beal Parkinson's disease Hum. Mol. Genet., October 15, 2007; 16(R2): R183 - R194. [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]
|
|
|
|
|
|
F. E. Herrera, S. Zucchelli, A. Jezierska, Z. S. Lavina, S. Gustincich, and P. Carloni On the Oligomeric State of DJ-1 Protein and Its Mutants Associated with Parkinson Disease: A COMBINED COMPUTATIONAL AND IN VITRO STUDY J. Biol. Chem., August 24, 2007; 282(34): 24905 - 24914. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Mandemakers, V. A. Morais, and B. De Strooper A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases J. Cell Sci., May 15, 2007; 120(10): 1707 - 1716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Gorner, E. Holtorf, J. Waak, T.-T. Pham, D. M. Vogt-Weisenhorn, W. Wurst, C. Haass, and P. J. Kahle Structural Determinants of the C-terminal Helix-Kink-Helix Motif Essential for Protein Stability and Survival Promoting Activity of DJ-1 J. Biol. Chem., May 4, 2007; 282(18): 13680 - 13691. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Jin, G. J. Li, J. Davis, D. Zhu, Y. Wang, C. Pan, and J. Zhang Identification of Novel Proteins Associated with Both {alpha}-Synuclein and DJ-1 Mol. Cell. Proteomics, May 1, 2007; 6(5): 845 - 859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Bier Antioxidants put Parkinson flies back in the PINK PNAS, September 5, 2006; 103(36): 13269 - 13270. [Full Text] [PDF]
|
|
|
|
|
|
B. Tang, H. Xiong, P. Sun, Y. Zhang, D. Wang, Z. Hu, Z. Zhu, H. Ma, Q. Pan, J.-h. Xia, et al. Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease Hum. Mol. Genet., June 1, 2006; 15(11): 1816 - 1825. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. K. Muqit, S. Gandhi, and N. W. Wood Mitochondria in Parkinson disease: back in fashion with a little help from genetics. Arch Neurol, May 1, 2006; 63(5): 649 - 654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Choi, M. C. Sullards, J. A. Olzmann, H. D. Rees, S. T. Weintraub, D. E. Bostwick, M. Gearing, A. I. Levey, L.-S. Chin, and L. Li Oxidative Damage of DJ-1 Is Linked to Sporadic Parkinson and Alzheimer Diseases J. Biol. Chem., April 21, 2006; 281(16): 10816 - 10824. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Gloeckner, N. Kinkl, A. Schumacher, R. J. Braun, E. O'Neill, T. Meitinger, W. Kolch, H. Prokisch, and M. Ueffing The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity Hum. Mol. Genet., January 15, 2006; 15(2): 223 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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 Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration PNAS, December 20, 2005; 102(51): 18676 - 18681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Li and M. F. Beal Leucine-rich repeat kinase 2: A new player with a familiar theme for Parkinson's disease pathogenesis PNAS, November 15, 2005; 102(46): 16535 - 16536. [Full Text] [PDF]
|
|
|
|
|
|
A. B. West, D. J. Moore, S. Biskup, A. Bugayenko, W. W. Smith, C. A. Ross, V. L. Dawson, and T. M. Dawson From The Cover: Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity PNAS, November 15, 2005; 102(46): 16842 - 16847. [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]
|
|
|
|
|
|
L. Zhang, M. Shimoji, B. Thomas, D. J. Moore, S.-W. Yu, N. I. Marupudi, R. Torp, I. A. Torgner, O. P. Ottersen, T. M. Dawson, et al. Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis Hum. Mol. Genet., July 15, 2005; 14(14): 2063 - 2073. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Xu, N. Zhong, H. Wang, J. E. Elias, C. Y. Kim, I. Woldman, C. Pifl, S. P. Gygi, C. Geula, and B. A. Yankner The Parkinson's disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis Hum. Mol. Genet., May 1, 2005; 14(9): 1231 - 1241. [Abstract] [Full Text] [PDF]
|
|