Human Molecular Genetics Advance Access originally published online on March 24, 2005
Human Molecular Genetics 2005 14(9):1231-1241; doi:10.1093/hmg/ddi134
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The Parkinson's disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis
1Department of Neurology, Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge St, Boston, MA 02135, USA, 2Department of Neurology, Harvard Medical School and Division of Neuroscience, The Children's Hospital, Boston, MA 02115, USA, 3Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA, 4Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090, Vienna, Austria and 5Laboratory for Neurodegenerative and Aging Research, Department of Medicine, Harvard Medical School and Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
* To whom correspondence should be addressed. Tel: +1 6177892935; Fax: +1 6177893111; Email: jin.xu{at}tufts.edu
Received December 30, 2004; Revised February 25, 2005; Accepted March 17, 2005
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 multifunctional 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. In addition, the transcriptional silencer PSF induces neuronal apoptosis, which 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 sensitizes cells to PSF-induced apoptosis. Both DJ-1 and p54nrb block oxidative stress and mutant 
-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.
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