Redox proteins in the defense against dopamine induced cell death

Abstract

Póster presentado en la Nordforsk C. elegans Network Meeting (Nordic Symposium), celebrada en Holte (Dinamarca) del 8 al 10 de marzo de 2013.[Background] Although the etiology of sporadic Parkinson disease (PD) is unknown, it is well established that oxidative stress plays an important role in the pathophysiology. The thioredoxin and glutaredoxin systems are two central systems upholding the sulfhydryl homeostasis by reducing disulfides and mixed disulfides within the cell and thereby protecting against oxidative stress. In the present study we used the dopamine metabolite 6-hydroxydopamine (6-OHDA) to model PD and to explore the protective effects of these two systems. The powerful neurotoxin 6-OHDA is highly prone to oxidation, resulting in the formation of the 6-OHDA-quinone, a highly reactive species.[Results] In human post-mortem PD brains the levels of thioredoxin 1 and thioredoxin reductase 1 were found to be significantly decreased. The neuroblastoma cellline SH-SYSY and the nematode C. elegans were used as model systems to evaluate the toxic effects of 6-0HDA. Selenite supplementation protected neuroblastoma cells against 6-0HDA, possibly by upregulating the selenoprotein thioredoxin reductase. A knock-down of thioredoxin and thioredoxin reductase by siRNA resulted in increased cell death in SH -SYSY. Furthermore, both the thioredoxin and the glutaredoxin systems were able to reduce 6-0HDA-quinone. The reduction required the dithiol mechanism as glutaredoxin with a mutation in the C-terminal cysteine ofthe active s i te was found to be ineffective at reducing 6-0HDA-quinone. To further investigate the protective role of proteins belonging to the thioredoxin system, experiments were conducted in C. elegans with 6-0HDA treatment ofnull mutants for trxr-1, trx4 or trx5 followed by evaluation of their neuronal integrity.[Conclusions] Our results suggest that the glutaredoxin and the thioredoxin systems appear to be important for neuro nal survival in dopamine induced cell death.Peer Reviewe