Abstract
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
Substances
-
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