Human Molecular Genetics Advance Access published online on June 8, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi211
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
* To whom correspondence should be addressed. Both homozygous (L166P, M26I, deletion) and heterozygous mutations (D149A, A104T) in the DJ-1 gene have been identified in Parkinson's disease (PD) patients. The biochemical function and subcellular localization of DJ-1 protein have not been clarified. To date the localization of DJ-1 protein has largely been described in studies over-expressing tagged DJ-1 protein in vitro. It is not known if the subcellular localization of over-expressed DJ-1 protein is identical to that of endogenously expressed DJ-1 protein both in vitro and in vivo. To clarify the subcellular localization and function of DJ-1, we generated three highly specific antibodies to DJ-1 protein and investigated the subcellular localization of endogenous DJ-1 protein in both mouse brain tissues and human neuroblastoma cells. We have found DJ-1 is widely distributed and is highly expressed in the brain. By cell fractionation and immunogold electron microscopy, we have identified an endogenous pool of DJ-1 in mitochondrial matrix and inter-membrane space. To further investigate if pathogenic mutations might prevent the distribution of DJ-1 to mitochondria, we generated human neuroblastoma cells stably transfected with wild-type or mutant (M26I, L166P, A104T, D149A) DJ-1 and performed mitochondrial fractionation and confocal co-localization imaging studies. Compared to wild-type and other mutants, L166P mutant exhibits largely reduced protein level. However, the pathogenic mutations do not alter the distribution of DJ-1 to mitochondria. Thus, DJ-1 is an integral mitochondrial protein that may have important functions in regulating mitochondrial physiology. Our findings of DJ-1's mitochondrial localization may have important implications for understanding the pathogenesis of PD.
Received March 16, 2005
Revised May 22, 2005
Accepted June 5, 2005
Article
Mitochondrial Localization of the Parkinson's Disease Related Protein DJ-1: Implications for Pathogenesis
2 Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo N-0317, Norway
3 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
4 Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N. Broadway, Suite 731, Baltimore, MD 21205, U.S.A.; Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Valina L. Dawson, E-mail: vdawson{at}jhmi.edu
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Godenschwege, R. Forde, C. P. Davis, A. Paul, K. Beckwith, and A. Duttaroy Mitochondrial Superoxide Radicals Differentially Affect Muscle Activity and Neural Function Genetics, September 1, 2009; 183(1): 175 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Blackinton, M. Lakshminarasimhan, K. J. Thomas, R. Ahmad, E. Greggio, A. S. Raza, M. R. Cookson, and M. A. Wilson Formation of a Stabilized Cysteine Sulfinic Acid Is Critical for the Mitochondrial Function of the Parkinsonism Protein DJ-1 J. Biol. Chem., March 6, 2009; 284(10): 6476 - 6485. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. S. Ko, R. Bailey, W. W. Smith, Z. Liu, J.-H. Shin, Y.-I. Lee, Y.-J. Zhang, H. Jiang, C. A. Ross, D. J. Moore, et al. CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity PNAS, February 24, 2009; 106(8): 2897 - 2902. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-F. Yuen, Y.-P. Chan, S. Law, G. Srivastava, M. El-tanani, T.-W. Mak, and K.-W. Chan DJ-1 Could Predict Worse Prognosis in Esophageal Squamous Cell Carcinoma Cancer Epidemiol. Biomarkers Prev., December 1, 2008; 17(12): 3593 - 3602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. van der Brug, J. Blackinton, J. Chandran, L.-Y. Hao, A. Lal, K. Mazan-Mamczarz, J. Martindale, C. Xie, R. Ahmad, K. J. Thomas, et al. RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways PNAS, July 22, 2008; 105(29): 10244 - 10249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yang, Y. Ouyang, L. Yang, M. F. Beal, A. McQuibban, H. Vogel, and B. Lu Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery PNAS, May 13, 2008; 105(19): 7070 - 7075. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Haque, K. J. Thomas, C. D'Souza, S. Callaghan, T. Kitada, R. S. Slack, P. Fraser, M. R. Cookson, A. Tandon, and D. S. Park Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP PNAS, February 5, 2008; 105(5): 1716 - 1721. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Yang, L. Chen, Y. Ding, X. Zhuang, and U. J. Kang Paraquat induces dopaminergic dysfunction and proteasome impairment in DJ-1-deficient mice Hum. Mol. Genet., December 1, 2007; 16(23): 2900 - 2910. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Exner, B. Treske, D. Paquet, K. Holmstrom, C. Schiesling, S. Gispert, I. Carballo-Carbajal, D. Berg, H.-H. Hoepken, T. Gasser, et al. Loss-of-Function of Human PINK1 Results in Mitochondrial Pathology and Can Be Rescued by Parkin J. Neurosci., November 7, 2007; 27(45): 12413 - 12418. [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]
|
|
|
|
|
|
E. Andres-Mateos, C. Perier, L. Zhang, B. Blanchard-Fillion, T. M. Greco, B. Thomas, H. S. Ko, M. Sasaki, H. Ischiropoulos, S. Przedborski, et al. DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase PNAS, September 11, 2007; 104(37): 14807 - 14812. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. I. Lucas and I. Marin A New Evolutionary Paradigm for the Parkinson Disease Gene DJ-1 Mol. Biol. Evol., February 1, 2007; 24(2): 551 - 561. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yang, S. Gehrke, Y. Imai, Z. Huang, Y. Ouyang, J.-W. Wang, L. Yang, M. F. Beal, H. Vogel, and B. Lu Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin PNAS, July 11, 2006; 103(28): 10793 - 10798. [Abstract] [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 D. J. Moore, V. L. Dawson, and T. M. Dawson Lessons from Drosophila Models of DJ-1 Deficiency Sci. Aging Knowl. Environ., January 11, 2006; 2006(2): pe2 - pe2. [Abstract] [Full Text]
|
|
|
|
|
|
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. Ooe, T. Taira, S. M. M. Iguchi-Ariga, and H. Ariga Induction of Reactive Oxygen Species by Bisphenol A and Abrogation of Bisphenol A-Induced Cell Injury by DJ-1 Toxicol. Sci., November 1, 2005; 88(1): 114 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Gandhi and N. W. Wood Molecular pathogenesis of Parkinson's disease Hum. Mol. Genet., September 15, 2005; 14(18): 2749 - 2755. [Abstract] [Full Text] [PDF]
|
|