Peroxiredoxins in the Central Nervous System
Asubio Pharma Co. Ltd. Research park, Institute of Integrated Medical Research Keio University, School of Medicine, Tokyo, Japan. Sub-cellular biochemistry
02/2007; 44:357-74. DOI: 10.1007/978-1-4020-6051-9_17
Oxidative stress is considered one of the causative pathomechanisms of nervous system diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke and excitotoxicity. The basal expression of six different peroxiredoxin (Prx) isozymes show distinct distribution profiles in different brain regions and different cell types. PrxI and VI are expressed in glial cells but not in neurons; while PrxII, III, IV and V are expressed in neurons. Various diseases or models show altered expression levels of these isozymes, such as by upregulation of PrxI, II and VI and downregulation of PrxIII. Thioredoxin (Trx)I mRNA is distributed widely in the rat brain. This distribution pattern may reflect the specific functions of these isozymes. Recently, the neuroprotective roles of Prx III and V against ibotenate-induced-excitotoxicity were reported by two independent groups. Adenovirus transduction of PrxIII eliminated protein nitration and prevented gliosis caused by direct infusion of ibotenate. Systemic administration of recombinant PrxV diminished brain lesions in animals treated with ibotenate. In this chapter, we review the causative mechanisms of oxidative stress in neurodegenerative diseases, as well as describe the basal and disease-induced changes in Prxs/Trxs/Trx reductases expression levels and neuroprotective roles of Trxs and Prxs as demonstrated in overexpression models.
Available from: Gethin J McBean
- "Basal expression of the six different Prx isozymes shows a distinctive distribution profile within brain regions and different cell types. On the one hand, Prx1 and 6 are expressed in glial cells but not in neurons; conversely, Prx2, 3, 4, and 5 are expressed in neurons . Of these enzymes, it is Prx3 that is found in mitochondria . "
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ABSTRACT: This review provides an overview of the biochemistry of thiol redox couples and the significance of thiol redox homeostasis in neurodegenerative disease. The discussion is centred on cysteine/cystine redox balance, the significance of the xc(-) cystine-glutamate exchanger and the association between protein thiol redox balance and neurodegeneration, with particular reference to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and glaucoma. The role of thiol disulphide oxidoreductases in providing neuroprotection is also discussed.
Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
Available from: Lawrence T Reiter
- "Alternatively, Notch inactivation could be a result of either degradation or abnormal processing of the endogenous presenilin in response to the expression of Psn along with the mammalian transgenes. Either possibility could have obvious disease relevance, as it seems clear that increased expression of these proteins occurs in AD brain (Krapfenbauer et al., 2003; Hattori and Oikawa, 2007), and our data suggest that such an increase in expression could have an impact on Presenilin function and therefore indirectly could influence plaque formation. "
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ABSTRACT: Alzheimer's disease (AD) pathogenesis is characterized by senile plaques in the brain and evidence of oxidative damage. Oxidative stress may precede plaque formation in AD; however, the link between oxidative damage and plaque formation remains unknown. Presenilins are transmembrane proteins in which mutations lead to accelerated plaque formation and early-onset familial Alzheimer's disease. Presenilins physically interact with two antioxidant enzymes thiol-specific antioxidant (TSA) and proliferation-associated gene (PAG) of the peroxiredoxin family. The functional consequences of these interactions are unclear. In the current study we expressed a presenilin transgene in Drosophila wing and sensory organ precursors of the fly. This caused phenotypes typical of Notch signaling loss-of-function mutations. We found that while expression of TSA or PAG alone produced no phenotype, co-expression of TSA and PAG with presenilin led to an enhanced Notch loss-of-function phenotype. This phenotype was more severe and more penetrant than that caused by the expression of Psn alone. In order to determine whether these phenotypes were indeed affecting Notch signaling, this experiment was performed in a genetic background carrying an activated Notch (Abruptex) allele. The phenotypes were almost completely rescued by this activated Notch allele. These results link peroxiredoxins with the in vivo function of Presenilin, which ultimately connects two key pathogenetic mechanisms in AD, namely, antioxidant activity and plaque formation, and raises the possibility of a role for peroxiredoxin family members in Alzheimer's pathogenesis.
Available from: Adair Roberto Soares Santos
- "Most of the work on peroxide metabolism in neural cells disregards the participation of Prx's [36,44–46]; however, the importance of Prx's in the central nervous system has begun to be recognized . Changes in the expression of Prx's or in the backup system (Trx/TrxR) are related to neuroprotection/neurotoxicity, as demonstrated in overexpression models, ischemia–reperfusion studies , and neurodegenerative models, providing evidence of the importance of Prx in neural cells   . However, in the central nervous system, little is known about the relative contributions of CAT, GPx, and especially Prx's to peroxide decomposition. "
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ABSTRACT: Cells are endowed with several overlapping peroxide-degrading systems whose relative importance is a matter of debate. In this study, three different sources of neural cells (rat hippocampal slices, rat C6 glioma cells, and mouse N2a neuroblastoma cells) were used as models to understand the relative contributions of individual peroxide-degrading systems. After a pretreatment (30 min) with specific inhibitors, each system was challenged with either H₂O₂ or cumene hydroperoxide (CuOOH), both at 100 μM. Hippocampal slices, C6 cells, and N2a cells showed a decrease in the H₂O₂ decomposition rate (23-28%) by a pretreatment with the catalase inhibitor aminotriazole. The inhibition of glutathione reductase (GR) by BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) significantly decreased H₂O₂ and CuOOH decomposition rates (31-77%). Inhibition of catalase was not as effective as BCNU at decreasing cell viability (MTT assay) and cell permeability or at increasing DNA damage (comet test). Impairing the thioredoxin (Trx)-dependent peroxiredoxin (Prx) recycling by thioredoxin reductase (TrxR) inhibition with auranofin neither potentiated peroxide toxicity nor decreased the peroxide-decomposition rate. The results indicate that neural peroxidatic systems depending on Trx/TrxR for recycling are not as important as those depending on GSH/GR. Dimer formation, which leads to Prx2 inactivation, was observed in hippocampal slices and N2a cells treated with H₂O₂, but not in C6 cells. However, Prx-SO₃ formation, another form of Prx inactivation, was observed in all neural cell types tested, indicating that redox-mediated signaling pathways can be modulated in neural cells. These differences in Prx2 dimerization suggest specific redox regulation mechanisms in glia-derived (C6) compared to neuron-derived (N2a) cells and hippocampal slices.
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