Abstract
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 alpha-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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis*
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DNA-Binding Proteins
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Genes, Recessive
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Genes, Reporter
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HeLa Cells
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Humans
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Intracellular Signaling Peptides and Proteins
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Mutation
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / pharmacology
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism*
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Neuroprotective Agents / metabolism
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Neuroprotective Agents / pharmacology
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Nuclear Matrix-Associated Proteins / metabolism
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Octamer Transcription Factors
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Oncogene Proteins / genetics*
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Oncogene Proteins / metabolism
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Oxidative Stress / drug effects
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PTB-Associated Splicing Factor
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Parkinson Disease / genetics*
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Parkinson Disease / metabolism
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Parkinson Disease / pathology
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Phosphoproteins / pharmacology
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Protein Deglycase DJ-1
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RNA, Small Interfering / metabolism
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RNA-Binding Proteins / metabolism
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RNA-Binding Proteins / pharmacology
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Synucleins
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Trans-Activators / genetics*
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Transfection
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alpha-Synuclein
Substances
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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NONO protein, human
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Nerve Tissue Proteins
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Neuroprotective Agents
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Nuclear Matrix-Associated Proteins
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Octamer Transcription Factors
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Oncogene Proteins
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PTB-Associated Splicing Factor
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Phosphoproteins
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RNA, Small Interfering
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RNA-Binding Proteins
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SNCA protein, human
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Synucleins
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Trans-Activators
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alpha-Synuclein
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PARK7 protein, human
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Protein Deglycase DJ-1