Parkinson disease-associated DJ-1 is required for the expression of the glial cell line-derived neurotrophic factor receptor RET in human neuroblastoma cells.
Mutations in PARK7/DJ-1 are associated with autosomal recessive, early onset Parkinson disease (PD). DJ-1 is an atypical peroxiredoxin-like peroxidase that may act as a redox-dependent chaperone and a regulator of transcription. Here we show that DJ-1 plays an essential role in the expression of rearranged during transfection (RET), a receptor for the glial cell line-derived neurotrophic factor, a neuroprotective molecule for dopaminergic neurons, the main target of degeneration in PD. The inducible loss of DJ-1 triggers the establishment of hypoxia and the production of reactive oxygen species that stabilize the hypoxia-inducible factor-1alpha (HIF-1a). HIF-1a expression is required for RET down-regulation. This study establishes for the first time a molecular link between the lack of functional DJ-1 and the glial cell line-derived neurotrophic factor signaling pathway that may explain the adult-onset loss of dopaminergic neurons. Furthermore, it suggests that hypoxia may play an important role in PD.
Foti
Rossana
R
Sector of Neurobiology, International School for Advanced Studies, Giovanni Armenise-Harvard Foundation Laboratory, AREA Science Park, SS 14, Km 163.5, Basovizza, Italy.
Zucchelli
Silvia
S
Biagioli
Marta
M
Roncaglia
Paola
P
Vilotti
Sandra
S
Calligaris
Raffaella
R
Krmac
Helena
H
Girardini
Javier Enrique
JE
Del Sal
Giannino
G
Gustincich
Stefano
S
D045744:Cell Line, Tumor; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D009154:Mutation; D009447:Neuroblastoma / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction; D000071617:Protein Deglycase DJ-1; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D017382:Reactive Oxygen Species; D015398:Signal Transduction
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D017382:Reactive Oxygen Species; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1
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