DJ-1 loss by glutaredoxin but not glutathione depletion triggers Daxx translocation and cell death.
Environmental and genetic causes are implicated in the etiopathogenesis of Parkinson's disease (PD), a neurodegenerative movement disorder. DJ-1, a putative gene recessively linked to early onset PD, functions as an antioxidant, transcriptional co-activator, and molecular chaperone. We examined DJ-1 status following global perturbation of protein thiol homeostasis by depleting cellular antioxidant glutathione or downregulating glutaredoxin 1, a thiol disulfide oxidoreductase, wherein both paradigms generate oxidative stress. While these perturbations did not affect expression of DJ-1 mRNA, downregulation of glutaredoxin 1 but not glutathione depletion caused loss of DJ-1 protein, translocation of Daxx (a death-associated protein) from nucleus, and cell death. Overexpression of wild-type DJ-1, but not the cysteine mutants, prevented Daxx translocation and cytotoxicity. Protease inhibitors prevented constitutive DJ-1 loss. Residual DJ-1 was present in reduced state, indicating that DJ-1 when oxidized was degraded through proteolysis. Thus, loss of DJ-1 occurring through its oxidative modification and subsequent proteolysis mediated through dysregulation of thiol disulfide oxidoreductase may contribute to pathogenesis of sporadic PD, thus providing a link between environmental challenges and constitutive levels of this vital protein.
Saeed
Uzma
U
Division of Cellular and Molecular Neurosciences, National Brain Research Centre , Nainwal Mode, Manesar, India.
Ray
Ajit
A
Valli
Rupanagudi Khader
RK
Kumar
A Madan Ram
AM
Ravindranath
Vijayalakshmi
V
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D002522:Chlorocebus aethiops; D056970:Co-Repressor Proteins; D054477:Glutaredoxins / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D000071617:Protein Deglycase DJ-1; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; C491473:Daxx protein, mouse; D054477:Glutaredoxins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D005978:Glutathione