The Parkinson's disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis

Hum Mol Genet. 2005 May 1;14(9):1231-41. doi: 10.1093/hmg/ddi134. Epub 2005 Mar 24.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis*
  • DNA-Binding Proteins
  • Genes, Recessive
  • Genes, Reporter
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / pharmacology
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology
  • Nuclear Matrix-Associated Proteins / metabolism
  • Octamer Transcription Factors
  • Oncogene Proteins / genetics*
  • Oncogene Proteins / metabolism
  • Oxidative Stress / drug effects
  • PTB-Associated Splicing Factor
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Phosphoproteins / pharmacology
  • Protein Deglycase DJ-1
  • RNA, Small Interfering / metabolism
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / pharmacology
  • Synucleins
  • Trans-Activators / genetics*
  • Transfection
  • alpha-Synuclein

Substances

  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • NONO protein, human
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Nuclear Matrix-Associated Proteins
  • Octamer Transcription Factors
  • Oncogene Proteins
  • PTB-Associated Splicing Factor
  • Phosphoproteins
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • SNCA protein, human
  • Synucleins
  • Trans-Activators
  • alpha-Synuclein
  • PARK7 protein, human
  • Protein Deglycase DJ-1