Human Molecular Genetics Advance Access published online on March 24, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi134
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge St, CBR4, Boston, MA 02135, USA; Department of Neurology, Harvard Medical School and Division of Neuroscience, The Children's Hospital, Boston, MA 02115, USA
* To whom correspondence should be addressed.
Article
The Parkinson's Disease Associated DJ-1 Protein is a Transcriptional Co-Activator that Protects Against Neuronal Apoptosis
2 Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA
3 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
4 Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090, Vienna, Austria
5 Laboratory for Neurodegenerative and Aging Research, Department of Medicine, Harvard Medical School and Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
6 Department of Neurology, Harvard Medical School and Division of Neuroscience, The Children's Hospital, Boston, MA 02115, USA
Jin Xu, E-mail: Jin.Xu{at}tufts.edu
Mutations in the DJ-1 gene cause early-onset autosomal recessive Parkinson's disease (PD), although the role of DJ-1 in the degeneration of dopaminergic neurons is unresolved. Here we show that the major interacting-proteins with DJ-1 in dopaminergic neuronal cells are the nuclear proteins p54nrb and pyrimidine tract-binding protein-associated splicing factor (PSF), two multi-functional regulators of transcription and RNA metabolism. PD-associated DJ-1 mutants exhibit decreased nuclear distribution and increased mitochondrial localization, resulting in diminished co-localization with co-activator p54nrb and repressor PSF. Unlike pathogenic DJ-1 mutants, wild-type DJ-1, acts to inhibit the transcriptional silencing activity of the PSF. Furthermore, the transcriptional silencer PSF induces neuronal apoptosis, that can be reversed by wild-type DJ-1, but to a lesser extent by PD-associated DJ-1 mutants. DJ-1-specific small interfering RNA(siRNA) sensitizes cells to PSF-induced apoptosis. Both DJ-1 and p54nrb block oxidative stress and mutant 
Abstract 
-synuclein induced cell death. Thus, DJ-1 is a neuroprotective transcriptional co-activator that may act in concert with p54nrb and PSF to regulate the expression of a neuroprotective genetic program. Mutations that impair the transcriptional co-activator function of DJ-1 render dopaminergic neurons vulnerable to apoptosis, and may contribute to the pathogenesis of PD.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Waak, S. S. Weber, A. Waldenmaier, K. Gorner, M. Alunni-Fabbroni, H. Schell, D. Vogt-Weisenhorn, T.-T. Pham, V. Reumers, V. Baekelandt, et al. Regulation of astrocyte inflammatory responses by the Parkinson's disease-associated gene DJ-1 FASEB J, August 1, 2009; 23(8): 2478 - 2489. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Waak, S. S. Weber, K. Gorner, C. Schall, H. Ichijo, T. Stehle, and P. J. Kahle Oxidizable Residues Mediating Protein Stability and Cytoprotective Interaction of DJ-1 with Apoptosis Signal-regulating Kinase 1 J. Biol. Chem., May 22, 2009; 284(21): 14245 - 14257. [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]
|
|
|
|
 |
|
 N. Zhong and J. Xu Synergistic activation of the human MnSOD promoter by DJ-1 and PGC-1{alpha}: regulation by SUMOylation and oxidation Hum. Mol. Genet., November 1, 2008; 17(21): 3357 - 3367. [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]
|
|
|
|
|
|
J. Fan, H. Ren, N. Jia, E. Fei, T. Zhou, P. Jiang, M. Wu, and G. Wang DJ-1 Decreases Bax Expression through Repressing p53 Transcriptional Activity J. Biol. Chem., February 15, 2008; 283(7): 4022 - 4030. [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 S. Kuwahara, A. Ikei, Y. Taguchi, Y. Tabuchi, N. Fujimoto, M. Obinata, S. Uesugi, and Y. Kurihara PSPC1, NONO, and SFPQ Are Expressed in Mouse Sertoli Cells and May Function as Coregulators of Androgen Receptor-Mediated Transcription Biol Reprod, September 1, 2006; 75(3): 352 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Zhong, C. Y. Kim, P. Rizzu, C. Geula, D. R. Porter, E. N. Pothos, F. Squitieri, P. Heutink, and J. Xu DJ-1 Transcriptionally Up-regulates the Human Tyrosine Hydroxylase by Inhibiting the Sumoylation of Pyrimidine Tract-binding Protein-associated Splicing Factor J. Biol. Chem., July 28, 2006; 281(30): 20940 - 20948. [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]
|
|
|
|
|
|
W. Zhou and C. R. Freed DJ-1 Up-regulates Glutathione Synthesis during Oxidative Stress and Inhibits A53T {alpha}-Synuclein Toxicity J. Biol. Chem., December 30, 2005; 280(52): 43150 - 43158. [Abstract] [Full Text] [PDF]
|
|