Peroxiredoxin-2 (Prx2) is a ubiquitously expressed thiol-dependent antioxidant enzyme that plays a critical role in protecting neurons from oxidative stress[@rhee2005][@kim2008]. As one of the most abundant peroxiredoxins in the brain, Prx2 is essential for maintaining redox homeostasis, modulating hydrogen peroxide (H₂O₂)-dependent signaling pathways, and providing neuroprotection in various pathological conditions[@wood2003]. The protein belongs to the typical 2-Cys peroxiredoxin subfamily, characterized by its ability to form intramolecular disulfide bonds during its catalytic cycle and to function as a homodimer[@hall2009].
The importance of Prx2 in neurodegeneration has become increasingly apparent through studies demonstrating its oxidative modification in Alzheimer's disease and Parkinson's disease brains, as well as its essential role in protecting dopaminergic neurons from cell death[@kim2011][@power2006]. Beyond its antioxidant function, Prx2 participates in various cellular processes including apoptosis regulation, inflammation modulation, and protein folding[@rhee2001]. The remarkable regenerative capacity of peroxiredoxins, involving the thioredoxin and glutaredoxin systems, allows Prx2 to catalyze hundreds of thousands of turnovers, making it one of the most efficient antioxidant enzymes in biological systems[@brown2013].
Prx2 adopts a characteristic thioredoxin fold structure that is highly conserved across the peroxiredoxin family[@karplus2007]. The protein consists of approximately 166 amino acids and forms a homodimer with each monomer contributing approximately 22 kDa to the complex. The dimerization interface involves extensive hydrophobic interactions and hydrogen bonding, creating a stable quaternary structure that is essential for enzymatic activity. Each monomer contains five α-helices and seven β-strands arranged in a characteristic thioredoxin-like fold[@hirotsu1999].
The catalytic mechanism of Prx2 centers on two conserved cysteine residues: the peroxidatic cysteine (Cys51) and the resolving cysteine (Cys172)[@poole2004]. During the catalytic cycle, the peroxidatic cysteine attacks the peroxide substrate, forming a sulfenic acid (Cys-SOH) intermediate. This reactive intermediate then condenses with the resolving cysteine to form an intramolecular disulfide bond, which is subsequently reduced by thioredoxin or other reductases to regenerate the active enzyme[@montemartini1998]. The presence of these two cysteines defines Prx2 as a typical 2-Cys peroxiredoxin, distinguishing it from atypical 2-Cys and 1-Cys variants that use different catalytic mechanisms.
The structural features of Prx2 also include a conserved Arg pocket that contributes to substrate binding and specificity[@tair2017]. The active site environment, particularly the presence of a "peroxidatic helix" and surrounding loop regions, facilitates the efficient reduction of hydrogen peroxide and organic hydroperoxides while preventing overoxidation of the catalytic cysteines. Additionally, Prx2 contains a C-terminal extension that contributes to dimer stabilization and may play roles in subcellular localization[@harris2012].
The catalytic cycle of Prx2 involves a series of precisely coordinated chemical transformations that enable efficient detoxification of reactive oxygen species[@rhee2011]. Upon encountering a peroxide substrate, the nucleophilic peroxidatic cysteine (Cys51) attacks the peroxide bond, resulting in the formation of a sulfenic acid intermediate and the release of water. This highly reactive sulfenic acid then rapidly condenses with the resolving cysteine (Cys172) to form a stable intramolecular disulfide bond[@yang2002]. The disulfide-bonded form of Prx2 is recognized by thioredoxin (Trx) or thioredoxin reductase systems, which provide the reducing equivalents necessary to regenerate the active dithiol form of the enzyme[@lee2008].
A unique feature of peroxiredoxins including Prx2 is their susceptibility to hyperoxidation, where the catalytic cysteine can be further oxidized to sulfinic (Cys-SO₂) or sulfonic (Cys-SO₃) acid forms under conditions of high oxidative stress[@yang2017]. While hyperoxidation temporarily inactivates the peroxidase activity, the enzyme can be regenerated by the sulfiredoxin (Srx) system, which uses ATP and reducing equivalents to convert the hyperoxidized cysteine back to the active sulfhydryl form[@biteau2003]. This hyperoxidation-induced inactivation may serve as a "floodgate" mechanism that allows H₂O₂ to accumulate and function as a signaling molecule when antioxidant defenses are overwhelmed.
Prx2 is expressed at high levels throughout the central nervous system, with particularly prominent expression in neurons of the cerebral cortex, hippocampus, and cerebellum[@sarafian2007]. The protein is localized to multiple subcellular compartments, including the cytoplasm, nucleus, mitochondria, and peroxisomes, reflecting its diverse functions in cellular redox homeostasis[@lim2008]. This broad subcellular distribution allows Prx2 to neutralize peroxides generated in different cellular compartments and to participate in compartment-specific redox signaling.
In neurons, Prx2 shows particular enrichment in synaptic regions, where it may play important roles in protecting synaptic components from oxidative damage[@jin2009]. The synaptic localization of Prx2, combined with its ability to interact with synaptic proteins, suggests functions beyond general antioxidant defense. Studies have demonstrated Prx2 association with synaptic vesicles, postsynaptic densities, and mitochondrial populations within synapses, positioning it to protect these critical neuronal structures from oxidative stress associated with neurotransmission and metabolic activity[@noh2012].
Prx2 serves as a primary defender against oxidative stress in neurons through its efficient scavenging of hydrogen peroxide and organic hydroperoxides[@dreij2015]. Unlike catalase, which is localized primarily to peroxisomes, Prx2's broad subcellular distribution allows it to neutralize peroxides throughout the cytoplasm, mitochondria, and nucleus. The enzyme exhibits remarkable substrate specificity for H₂O₂ but can also reduce organic peroxides including lipid hydroperoxides, providing comprehensive protection against various forms of oxidative damage[@fujii2012].
The importance of Prx2 in neuronal antioxidant defense is highlighted by studies demonstrating that Prx2 knockdown sensitizes neurons to oxidative stress-induced cell death, while Prx2 overexpression provides robust neuroprotection against various insults[@kim2014]. In the context of excitotoxicity, which involves excessive glutamate receptor activation and consequent oxidative stress, Prx2 has been shown to protect neurons by preventing mitochondrial dysfunction and caspase activation[@hu2011]. These findings suggest that Prx2 represents a critical component of the neuronal antioxidant defense system.
Beyond its role in detoxification, Prx2 functions as a key modulator of H₂O₂-dependent signaling pathways[@rhee2001a]. Unlike its role as a scavenger, where it removes H₂O₂ to prevent oxidative damage, Prx2's involvement in signaling involves the controlled generation and removal of H₂O₂ as a second messenger. The catalytic cycle of Prx2, particularly its hyperoxidation and regeneration, allows for dynamic regulation of local H₂O₂ concentrations and the modulation of redox-sensitive signaling pathways[@veal2007].
Prx2 interacts with and regulates various kinases and transcription factors that are sensitive to cellular redox state. For example, Prx2 has been shown to regulate MAPK signaling pathways including JNK, p38, and ERK, which are involved in cell survival, stress responses, and synaptic plasticity[@kim2009]. Additionally, Prx2 can directly interact with the NF-κB signaling pathway, influencing inflammatory gene expression in glial cells and neurons[@jin2009a]. This signaling regulatory function positions Prx2 at the interface between antioxidant defense and cellular signaling.
In neurodegenerative diseases, Prx2 plays complex roles that extend beyond simple antioxidant protection. In Alzheimer's disease, Prx2 is oxidatively modified and functionally impaired in affected brain regions[@cifuentes2012]. The oxidation of Prx2 may contribute to the increased oxidative stress observed in AD brains and create a vicious cycle where impaired antioxidant defenses lead to further oxidative damage. Interestingly, some studies suggest that Prx2 oxidation may be an early event in AD pathogenesis, potentially serving as a biomarker or therapeutic target[@reed2009].
In Parkinson's disease, Prx2 has been shown to be particularly important for the survival of dopaminergic neurons in the substantia nigra[@rizwan2019]. These neurons are especially vulnerable to oxidative stress due to their high metabolic activity, dopamine oxidation, and mitochondrial dysfunction. Prx2 knockout mice show increased sensitivity to PD-relevant toxins and develop more severe parkinsonian phenotypes, while Prx2 overexpression protects dopaminergic neurons from cell death[@kwon2015]. These findings highlight the critical neuroprotective function of Prx2 in PD.
The central role of Prx2 in neuroprotection has generated interest in developing therapeutic strategies that enhance Prx2 function or expression in neurodegenerative diseases[@kim2020]. Several approaches are being explored, including small molecules that activate peroxiredoxin activity, compounds that reduce Prx2 oxidation, and gene therapy approaches to increase Prx2 expression in the brain[@cao2021]. The sulfiredoxin system, which regenerates hyperoxidized Prx2, represents another potential therapeutic target, as enhancing its activity could restore peroxidase function under conditions of high oxidative stress.
Beyond direct targeting of Prx2, strategies to increase cellular reducing power through the thioredoxin or glutaredoxin systems may indirectly enhance Prx2 function[@arner2000]. Natural compounds found in foods and beverages, including sulforaphane and other Nrf2 activators, have been shown to upregulate peroxiredoxin expression through the antioxidant response element, providing a potential dietary intervention strategy[@zhang2015]. Clinical trials exploring these approaches in neurodegenerative diseases are ongoing, with biomarkers of redox status serving as outcome measures.