Nuclear translocation of DJ-1 during oxidative stress-induced neuronal cell death.
Loss-of-function mutations in the PARK7/DJ-1 gene cause early onset autosomal-recessive Parkinson disease. DJ-1 has been implicated in protection of neurons from oxidative stress and in regulation of transcriptional activity. However, whether there is a relationship between the subcellular localization of DJ-1 and its function remains unknown. Therefore, we examined the ... subcellular localization of DJ-1 during dopaminergic neurodegeneration induced by various insults. Immunoblotting and immunocytochemistry showed that the nuclear pool of DJ-1 dramatically increased in both MN9D dopaminergic neuronal cells and primary cultures of mesencephalic dopaminergic neurons after 6-hydroxydopamine (6-OHDA) treatment. This was paralleled by a corresponding decrease in its cytosolic level, indicating drug-induced nuclear translocation of DJ-1. The same phenomenon was detected in other cell death paradigms induced by pro-oxidants including hydrogen peroxide and cupric chloride. Consequently, cotreatment with the antioxidant N-acetyl-l-cysteine blocked the translocation of DJ-1 into the nucleus. However, mutation at cysteine 106 had no effect on the translocation of DJ-1 into the nucleus, suggesting that reactive oxygen species-mediated downstream signaling and/or modifications other than oxidative modification are involved in its nuclear translocation. Ectopic expression of nucleus localization signal (NLS)-tagged DJ-1 prevented cell death from 6-OHDA. We investigated whether nuclear DJ-1 was involved in transcriptional regulation and found that DJ-1 was localized in promyelocytic leukemia bodies, and this localization increased upon 6-OHDA treatment. We also confirmed that binding of DJ-1 and promyelocytic leukemia bodies indeed increased after 6-OHDA treatment. Consequently, expression levels of acetylated p53 and PUMA were downregulated in cells overexpressing DJ-1 or NLS-tagged DJ-1. Taken together, our data suggest that nuclear translocation of DJ-1 may protect neurons from cell death after oxidative stress.
Mesh Terms:
Acetylcysteine, Active Transport, Cell Nucleus, Animals, Antioxidants, Apoptosis, Apoptosis Regulatory Proteins, Caspase 3, Cells, Cultured, Copper, Dopaminergic Neurons, Humans, Intracellular Signaling Peptides and Proteins, Mice, Oncogene Proteins, Oxidants, Oxidative Stress, Oxidopamine, Primary Cell Culture, Proto-Oncogene Proteins, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species
Acetylcysteine, Active Transport, Cell Nucleus, Animals, Antioxidants, Apoptosis, Apoptosis Regulatory Proteins, Caspase 3, Cells, Cultured, Copper, Dopaminergic Neurons, Humans, Intracellular Signaling Peptides and Proteins, Mice, Oncogene Proteins, Oxidants, Oxidative Stress, Oxidopamine, Primary Cell Culture, Proto-Oncogene Proteins, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species
Free Radic. Biol. Med.
Date: Aug. 15, 2012
PubMed ID: 22683601
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