title: Protective effects of the thioredoxin and glutaredoxin systems in dopamine-induced cell death.
abstract: Although the etiology of sporadic Parkinson disease (PD) is unknown, it is well established that oxidative stress plays an important role in the pathogenic mechanism. The thioredoxin (Trx) and glutaredoxin (Grx) systems are two central systems upholding the sulfhydryl homeostasis by reducing disulfides and mixed disulfides within the cell and thereby protecting against oxidative stress. By examining the expression of redox proteins in human postmortem PD brains, we found the levels of Trx1 and thioredoxin reductase 1 (TrxR1) to be significantly decreased. The human neuroblastoma cell line SH-SY5Y and the nematode Caenorhabditis elegans were used as model systems to explore the potential protective effects of the redox proteins against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. 6-OHDA is highly prone to oxidation, resulting in the formation of the quinone of 6-OHDA, a highly reactive species and powerful neurotoxin. Treatment of human cells with 6-OHDA resulted in an increased expression of Trx1, TrxR1, Grx1, and Grx2, and small interfering RNA for these genes significantly increased the cytotoxic effects exerted by the 6-OHDA neurotoxin. Evaluation of the dopaminergic neurons in C. elegans revealed that nematodes lacking trxr-1 were significantly more sensitive to 6-OHDA, with significantly increased neuronal degradation. Importantly, both the Trx and the Grx systems were also found to directly mediate reduction of the 6-OHDA-quinone in vitro and thus render its cytotoxic effects. In conclusion, our results suggest that the two redox systems are important for neuronal survival in dopamine-induced cell death.
authors.affiliation: Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Arodin
authors.affiliation: Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Miranda-Vizuete
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Novum, SE-141 83 Huddinge, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Swoboda
authors.affiliation: Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden; Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: aristi.fernandes@ki.se.
authors.forename: Aristi P
authors.initials: AP
authors.lastname: Fernandes
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D017173:Caenorhabditis elegans / Q000201:enzymology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000494:pharmacology; D054477:Glutaredoxins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009498:Neurotoxins / Q000096:biosynthesis / Q000633:toxicity; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000235:genetics; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D054481:Thioredoxin Reductase 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013879:Thioredoxins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D054477:Glutaredoxins; D009498:Neurotoxins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013879:Thioredoxins; D016627:Oxidopamine; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D004298:Dopamine
keywords: 6-Hydroxydopamine; Glutaredoxin; Neuronal degeneration; Thioredoxin; Thioredoxin reductase