Peroxiredoxin expression in the central nervous system and oxidative modifications : potential role in neurodegeneration

(eng) With its large oxygen consumption, the brain is exposed to oxidative stress which is also thought to contribute to neuron loss in neurodegenerative diseases (NDDs). A tight regulation of intracellular levels of reactive oxygen and nitrogen species is thus needed to maintain redox homeostasis. The role of peroxiredoxins (Prdxs) in this regulation is currently believed to be central among cellular peroxidases. To better understand the functions of Prdxs in the brain, we used immunohistochemistry to study the distribution of the six mammalian members (Prdx1-6) in cell types and regions of the mouse brain. Prdx2-5 were found in neurons and Prdx1, 4 and 6 in glia. The brain regional analysis also revealed an uneven distribution among neuronal populations. Interestingly, areas affected in NDDs exhibit particularly low levels of Prdxs. This could contribute to the specific vulnerability of these neurons. Moreover, while Prdx impairment in Parkinson's disease is thought to occur through posttranslational modifications, we showed that Prdxs undergo hyperoxidation in neuroblastoma cells upon exposure to peroxynitrite donor SIN-1, but not with the respiratory inhibitor MPP+. This provides the first evidence of Prdx hyperoxidation by peroxynitrite. We also confirmed a divergent sensitivity to hyperoxidation among Prdxs. Prdx5 is the only isoform for which no KO mice and no Prdx5 overexpressing mice exist, thereby limiting the study of Prdx5 in vivo functions. The first stages for the generation of Prdx5 transgenic mouse models are reported here. However, additional work will be necessary to obtain and characterize the transgenic animals. In conclusion, though Prdx1-6 are all peroxide scavengers, our work reinforces the idea that they may be complementary in the brain as a result of their different substrate specificity, cellular/subcellular localization and posttranslational regulation.