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Transgenic overexpression of peroxiredoxin-2 attenuates ischemic neuronal injury via suppression of a redox-sensitive pro-death signaling pathway.

ABSTRACT: Peroxiredoxins (PRXs) are a newly characterized family of peroxide scavenging enzymes that not only help maintain cellular redox homeostasis but also may directly engage in a variety of intracellular signaling pathways. PRX2 is a neuronal-specific PRX believed to participate in cerebral antioxidant responses in several neurodegenerative diseases. This study investigates the potential neuroprotective effect and the underlying mechanism of PRX2 in models of ischemic neuronal injury.Transgenic mice overexpressing PRX2 showed reduced brain injury and improved neurological recovery up to 3 weeks after transient focal cerebral ischemia compared to wild-type littermates. In primary cultures of cortical neurons, transfection of PRX2 but not the loss-of-catalytic-site PRX2 mutant conferred neuroprotection against cell death induced by oxygen glucose deprivation. PRX2 exhibited potent pro-survival effects in ischemic neurons by maintaining thioredoxin (Trx) in its reduced state, thereby preventing oxidative stress-mediated activation of apoptosis signal-regulating kinase 1 (ASK1) and the downstream MKK/JNK pro-death signaling pathway. PRX2 failed to provide additional neuroprotection against ischemic injury in Trx- or ASK1-knockdown neuron cultures and in mice treated with a JNK inhibitor.This study provides evidence that neuronal overexpression of PRX2 confers prolonged neuroprotection against ischemic/reperfusion brain injury. Moreover, the results suggest a signaling pathway by which PRX2 suppresses ischemia-induced neuronal apoptosis.Enhanced neuronal expression and activity of PRX2 protect against ischemic neuronal injury by directly modulating the redox-sensitive Trx-ASK1 signaling complex.

SUBMITTER: Gan Y

PROVIDER: S-EPMC3387778 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Transgenic overexpression of peroxiredoxin-2 attenuates ischemic neuronal injury via suppression of a redox-sensitive pro-death signaling pathway.

Gan Yu Y Ji Xunming X Hu Xiaoming X Luo Yumin Y Zhang Lili L Li Peiying P Liu Xiangrong X Yan Feng F Vosler Peter P Gao Yanqin Y Stetler R Anne RA Chen Jun J

Antioxidants & redox signaling 20120514 5

<h4>Aims</h4>Peroxiredoxins (PRXs) are a newly characterized family of peroxide scavenging enzymes that not only help maintain cellular redox homeostasis but also may directly engage in a variety of intracellular signaling pathways. PRX2 is a neuronal-specific PRX believed to participate in cerebral antioxidant responses in several neurodegenerative diseases. This study investigates the potential neuroprotective effect and the underlying mechanism of PRX2 in models of ischemic neuronal injury.<h ...[more]

PMID: 22356734

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Project description:Backgroundp23 belongs to the highly conserved p24 family of type I transmembrane proteins, which participate in the bidirectional protein transport between the endoplasmic reticulum and Golgi apparatus. Mammalian p23 has been shown to interact with ?-secretase complex, and modulate secretory trafficking as well as intramembranous processing of amyloid precursor protein in cultured cells. Negative modulation of ?-amyloid production by p23 in cultured cell lines suggested that elevation of p23 expression in neurons might mitigate cerebral amyloid burden.ResultsWe generated several lines of transgenic mice expressing human p23 in neurons under the control of Thy-1.2 promoter. We found that even a 50% increase in p23 levels in the central nervous system of mice causes post-natal growth retardation, severe neurological problems characterized by tremors, seizure, ataxia, and uncoordinated movements, and premature death. The severity of the phenotype closely correlated with the level of p23 overexpression in multiple transgenic lines. While the number and general morphology of neurons in Hup23 mice appeared to be normal throughout the brain, abnormal non-Golgi p23 localization was observed in a subset of neurons with high transgene expression in brainstem. Moreover, detailed immunofluorescence analysis revealed marked proliferation of astrocytes, activation of microglia, and thinning of myelinated bundles in brainstem of Hup23 mice.ConclusionsThese results demonstrate that proper level of p23 expression is critical for neuronal function, and perturbing p23 function by overexpression initiates a cascade of cellular reactions in brainstem that leads to severe motor deficits and other neurological problems, which culminate in premature death. The neurological phenotype observed in Hup23 mice highlights significant adverse effects associated with manipulating neuronal expression of p23, a previously described negative modulator of ?-secretase activity and ?-amyloid production. Moreover, our report has broader relevance to molecular mechanisms in several neurodegenerative diseases as it highlights the inherent vulnerability of the early secretory pathway mechanisms that ensure proteostasis in neurons.

Dataset Information

Transgenic overexpression of peroxiredoxin-2 attenuates ischemic neuronal injury via suppression of a redox-sensitive pro-death signaling pathway.

Publications

Transgenic overexpression of peroxiredoxin-2 attenuates ischemic neuronal injury via suppression of a redox-sensitive pro-death signaling pathway.

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