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.

Aggresome-forming TTRAP mediates pro-apoptotic properties of Parkinson's disease-associated DJ-1 missense mutations / Zucchelli, S; Vilotti, Sandra; Calligaris, R; Lavina, Zs; Biagioli, M; Foti, R; DE MASO, L; Pinto, M; Gorza, M; Speretta, E; Casseler, C; Tell, G; DEL SAL, G; Gustincich, Stefano. - In: CELL DEATH AND DIFFERENTIATION. - ISSN 1350-9047. - 16:1(2009), pp. 428-438. [10.1038/cdd.2008.169]

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

ZUCCHELLI S;Vilotti, Sandra;Gustincich, Stefano
2009-01-01

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.
2009
16
1
428
438
http://www.nature.com/doifinder/10.1038/cdd.2008.169
Zucchelli, S; Vilotti, Sandra; Calligaris, R; Lavina, Zs; Biagioli, M; Foti, R; DE MASO, L; Pinto, M; Gorza, M; Speretta, E; Casseler, C; Tell, G; DEL...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11767/16819
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