Aggresome-forming TTRAP mediates pro-apoptotic properties of Parkinson's disease-associated DJ-1 missense mutations.
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.
Zucchelli
S
S
Sector of Neurobiology, International School for Advanced Studies (SISSA), AREA Science Park, Basovizza, Trieste 34012, Italy.
Vilotti
S
S
Calligaris
R
R
Lavina
Z S
ZS
Biagioli
M
M
Foti
R
R
De Maso
L
L
Pinto
M
M
Gorza
M
M
Speretta
E
E
Casseler
C
C
Tell
G
G
Del Sal
G
G
Gustincich
S
S
D000970:Antineoplastic Agents / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D001932:Brain Neoplasms; D002460:Cell Line; D004268:DNA-Binding Proteins; D004298:Dopamine / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007976:Leupeptins / Q000378:metabolism; D020125:Mutation, Missense; D009447:Neuroblastoma; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases; D011485:Protein Binding; D000071617:Protein Deglycase DJ-1; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007976:Leupeptins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D014157:Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D010727:Phosphoric Diester Hydrolases; C474866:TDP2 protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D004298:Dopamine