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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
Source: PubMed

ABSTRACT 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.

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    • "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 [99]. Of these enzymes, it is Prx3 that is found in mitochondria . "
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    • "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.
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    • "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 [47]. 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 [47] [48] [49]. 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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