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.
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Abbreviations
- PD:
-
Parkinson's disease
- TTRAP:
-
TRAF and TNF receptor-associated protein
- UCH-L1:
-
ubiquitin C-terminal hydrolase-L1
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Acknowledgements
We are indebted to Dr. Patrizia Rizzu (University Medical Center, Amsterdam, The Netherlands) for kindly providing human DJ-1 cDNA clone; to Dr. Francesca Persichetti (SISSA, Trieste, Italy) for LexA-Rrs1 plasmid and for carefully reading the manuscript and to Dr. Licio Collavin (University of Trieste, Italy) for antibodies, constructs and helpful discussions. We thank all the members of the SG lab for thought-provoking discussions and help. This work was supported by the Telethon Grant GGP06268, by The Giovanni Armenise-Harvard Foundation and by the Italian Institute of Technology.
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Zucchelli, S., Vilotti, S., Calligaris, R. et al. Aggresome-forming TTRAP mediates pro-apoptotic properties of Parkinson's disease-associated DJ-1 missense mutations. Cell Death Differ 16, 428–438 (2009). https://doi.org/10.1038/cdd.2008.169
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DOI: https://doi.org/10.1038/cdd.2008.169
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