The Parkinson's disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis.
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.
Mesh Terms:
Apoptosis, Genes, Recessive, Genes, Reporter, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Mutation, Nerve Tissue Proteins, Neurons, Neuroprotective Agents, Nuclear Matrix-Associated Proteins, Octamer Transcription Factors, Oncogene Proteins, Oxidative Stress, Parkinson Disease, Phosphoproteins, RNA, Small Interfering, RNA-Binding Proteins, Synucleins, Trans-Activators, Transfection, alpha-Synuclein
Apoptosis, Genes, Recessive, Genes, Reporter, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Mutation, Nerve Tissue Proteins, Neurons, Neuroprotective Agents, Nuclear Matrix-Associated Proteins, Octamer Transcription Factors, Oncogene Proteins, Oxidative Stress, Parkinson Disease, Phosphoproteins, RNA, Small Interfering, RNA-Binding Proteins, Synucleins, Trans-Activators, Transfection, alpha-Synuclein
Hum. Mol. Genet.
Date: May. 01, 2005
PubMed ID: 15790595
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