Aggresome-forming TTRAP mediates pro-apoptotic properties of Parkinson's disease-associated DJ-1 missense mutations

Cell Death Differ. 2009 Mar;16(3):428-38. doi: 10.1038/cdd.2008.169. Epub 2008 Nov 21.


Mutations in PARK7 DJ-1 have been associated with autosomal-recessive early-onset Parkinson's disease (PD). This gene encodes for an atypical peroxiredoxin-like peroxidase that may act as a regulator of transcription and a redox-dependent chaperone. Although large gene deletions have been associated with a loss-of-function phenotype, the pathogenic mechanism of several missense mutations is less clear. By performing a yeast two-hybrid screening from a human fetal brain library, we identified TRAF and TNF receptor-associated protein (TTRAP), an ubiquitin-binding domain-containing protein, as a novel DJ-1 interactor, which was able to bind the PD-associated mutations M26I and L166P more strongly than wild type. TTRAP protected neuroblastoma cells from apoptosis induced by proteasome impairment. In these conditions, endogenous TTRAP relocalized to a detergent-insoluble fraction and formed cytoplasmic aggresome-like structures. Interestingly, both DJ-1 mutants blocked the TTRAP protective activity unmasking a c-jun N-terminal kinase (JNK)- and p38-MAPK (mitogen-activated protein kinase)-mediated apoptosis. These results suggest an active role of DJ-1 missense mutants in the control of cell death and position TTRAP as a new player in the arena of neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / metabolism
  • Apoptosis / physiology*
  • Brain Neoplasms
  • Cell Line
  • DNA-Binding Proteins
  • Dopamine / metabolism
  • Enzyme Activation
  • Humans
  • Inclusion Bodies / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Leupeptins / metabolism
  • Mutation, Missense*
  • Neuroblastoma
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins / genetics*
  • Oncogene Proteins / metabolism
  • Oxidative Stress
  • Parkinson Disease* / genetics
  • Parkinson Disease* / metabolism
  • Phosphoric Diester Hydrolases
  • Protein Binding
  • Protein Deglycase DJ-1
  • Substantia Nigra / cytology
  • Substantia Nigra / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Two-Hybrid System Techniques
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Leupeptins
  • Nuclear Proteins
  • Oncogene Proteins
  • Transcription Factors
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • PARK7 protein, human
  • Protein Deglycase DJ-1
  • Phosphoric Diester Hydrolases
  • TDP2 protein, human
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde
  • Dopamine