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.
Xu
Jin
J
Department of Neurology, Caritas St Elizabeth's Center, Tufts University School of Medicine, Boston, MA 02135, USA. jin.xu@tufts.edu
Zhong
Nan
N
Wang
Haoyong
H
Elias
Joshua E
JE
Kim
Christina Y
CY
Woldman
Irina
I
Pifl
Christian
C
Gygi
Steven P
SP
Geula
Changiz
C
Yankner
Bruce A
BA
D017209:Apoptosis; D004268:DNA-Binding Proteins; D005808:Genes, Recessive; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism; D050810:Octamer Transcription Factors; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000072670:PTB-Associated Splicing Factor; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000494:pharmacology; D000071617:Protein Deglycase DJ-1; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism / Q000494:pharmacology; D051843:Synucleins; D015534:Trans-Activators / Q000235:genetics*; D014162:Transfection; D051844:alpha-Synuclein
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C083214:NONO protein, human; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D034521:Nuclear Matrix-Associated Proteins; D050810:Octamer Transcription Factors; D015513:Oncogene Proteins; D000072670:PTB-Associated Splicing Factor; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C497604:SNCA protein, human; D051843:Synucleins; D015534:Trans-Activators; D051844:alpha-Synuclein; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1