Keap1-Nrf2 activation in the presence and absence of DJ-1.
The molecular mechanisms leading to neurodegeneration in Parkinson's disease remain elusive. Deletion and mutations of DJ-1 (PARK7) have been reported to cause autosomal recessive familial Parkinson's disease. Wildtype DJ-1 scavenges H(2)O(2) by cysteine oxidation in response to oxidative stress, and thus confers neuroprotection. Activation of the transcription factor NF-E2-related factor-2 (Nrf2) has also been shown to be important for protection against oxidative stress in many models of neurodegenerative diseases. Previous data indicate that DJ-1 affects the transcriptional functions and stability of Nrf2. However, this observation has not been confirmed. In the current study, the role of DJ-1 in the regulation of Nrf2 is examined in primary cultured neurons, astrocytes and in vivo. The prototypical Nrf2 activator tBHQ protected primary cortical neurons derived from DJ-1-knockout (KO) as well as DJ-1 wildtype mice by activation of Nrf2-ARE pathway. Nrf2 nuclear translocation, robust increases in canonical Nrf2-driven genes and proteins, and dramatic activation of the ARE reporter gene, hPAP, were observed after tBHQ treatment. These results were further confirmed by siRNA-mediated DJ-1 knockdown in primary cortical astrocytes from ARE-hPAP mice and tBHQ administration into the striatum of mouse brain. In addition, overexpression of Nrf2 with adenovirus preferentially in astrocytes from DJ-1-KO mice enhanced survival of neurons under oxidative insults. These findings indicate that activation of the Nrf2-ARE pathway is independent of DJ-1, and Nrf2 activation is a potential therapeutic target to prevent neurodegeneration in sporadic and DJ-1 familial Parkinson's disease.
Gan
Li
L
School of Pharmacy, 6125 Rennebohm Hall, University of Wisconsin-Madison, Madison, WI 53705-2222, USA.
Johnson
Delinda A
DA
Johnson
Jeffrey A
JA
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D001253:Astrocytes / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D020287:In Situ Nick-End Labeling / Q000379:methods; D007527:Isoenzymes / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009281:Naphthalenes; D009474:Neurons / Q000502:physiology; D015513:Oncogene Proteins / Q000172:deficiency*; D010082:Oxepins; D018384:Oxidative Stress / Q000187:drug effects; D054464:Peroxiredoxins; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D000071617:Protein Deglycase DJ-1; D034741:RNA, Small Interfering / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection / Q000379:methods
C461941:1-phenyl-1,4-epoxy-1H,4H-naphtho(1,8-de)(1,2)dioxepin; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D006873:Hydroquinones; D007527:Isoenzymes; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D009281:Naphthalenes; C495636:Nfe2l2 protein, mouse; D015513:Oncogene Proteins; D010082:Oxepins; D034741:RNA, Small Interfering; C018855:2-tert-butylhydroquinone; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D000469:Alkaline Phosphatase; C019839:alkaline phosphatase, placental; D005978:Glutathione