The role of NADPH oxidase (NOX) enzymes in neurodegenerative disease

doi:10.1007/s11515-012-1250-y

Front Biol

2013, Vol. 8

Issue (2) : 175-188 https://doi.org/10.1007/s11515-012-1250-y

REVIEW

The role of NADPH oxidase (NOX) enzymes in neurodegenerative disease

Abiodun AJAYI, Xin YU, Anna-Lena STR?M(

)

Department of Neurochemistry, Stockholm University, 10691 Stockholm, Sweden

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Abstract

Recently, mounting evidence implicating reactive oxygen species (ROS) generated by NADPH oxidase (NOX) enzymes in the pathogenesis of several neurodegenerative diseases including Amyotrophic lateral sclerosis (ALS), Alzheimer’s (AD), Parkinson’s (PD) and polyglutamine disease, have arisen. NOX enzymes are transmembrane proteins and generate reactive oxygen species by transporting electrons across lipid membranes. Under normal healthy conditions, low levels of ROS produced by NOX enzymes have been shown to play a role in neuronal differentiation and synaptic plasticity. However, in chronic neurodegenerative diseases over-activation of NOX in neurons, as well as in astrocytes and microglia, has been linked to pathogenic processes such as oxidative stress, exitotoxicity and neuroinflammation. In this review, we summarize the current knowledge about NOX functions in the healthy central nervous system and especially the role of NOX enzymes in neurodegenerative disease processes.

Keywords neurodegeneration oxidative stress NADPH oxidase microglia inflammation

Corresponding Author(s): STR?M Anna-Lena,Email:anna-lena.strom@neurochem.su.se

Issue Date: 01 April 2013

Cite this article:

Abiodun AJAYI,Xin YU,Anna-Lena STR?M. The role of NADPH oxidase (NOX) enzymes in neurodegenerative disease[J]. Front Biol, 2013, 8(2): 175-188.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-012-1250-y
https://academic.hep.com.cn/fib/EN/Y2013/V8/I2/175

Fig.1 The NOX family members and their activation. (A) Schematic diagrams of the NADPH oxidases and their regulatory subunits. The p22phox subunit interacts with NOX1-4. NOX2 activation also involves association with rac, p47phox, p67phox and p40phox. NOX1 activity is believed to primarily involve association with rac, NOXO1 and NOXA1. However, the p47phox and p67phox can replace NOXO1 and NOXA1, respectively. NOX3 subunit dependency is less characterized, but activity is believed to involve rac, p47phox and NOXA1. NOX4 is constitutively active, but the activity is stimulated by p22phox. NOX5 and DUOX1/2 containEF-hands (EF) and are activated by Ca binding. DUOX 1/2 also requires the association with DUOX maturation factors A1/2, respectively. (B) Summary of some key stimuli and pathways known to activate NOX enzymes in various cell types. Translocation of cytosolic regulatory subunits play an essential role in activation of NOX1-3. During NOX2 activation, the translocation of p47phox is controlled by a stepwise phosphorylation of p47phox. PKC, which can be activated by multiple pathways, including increased cytosolic Ca levels, is one important kinase responsible for p47phox phosphorylation. Other kinases involved include Akt and MAPKs (ERK1/2 and p38), which can beactivated by signaling from receptor tyrosine kinases (RTKs) including the insulin, Trk, PDGF and VEGF receptors. NOX2 activation also involves Rac translocation, and this step is controlled by phosphorylation of GDP dissociation inhibitors (GDIs) by src and possibly PKC. Elevated cytoplasmic Ca concentrations, through opening of membrane ion channels or intracellular stores, are a key in NOX5 and DUOX1/2 activation. TGF-β receptor signaling has been shown to induceexpression of NOX4 on both the endoplasmic reticulum and the plasma membrane. Transcription of NOX4 can also be induced by RTK signaling. NOX enzymes have also been reported to interact with and be activated by adaptor proteins involved in Toll-like receptor (TLR) and cytokine receptor (CR) signaling.

Fig.2 Cellular signaling by NOX enzymes. The ROS produced by NOX enzymes affect a number of redox-sensitive molecules, including protein tyrosine phosphatases (PTPs), dual-specificity phosphatases (DSPs), and transcription factors such as AP-1, NFAT, NF-?B, HIF-1 and p53. Other redox sensitive targets include the apoptosis signal-regulating kinase 1 (ASK1) and the tyrosine-protein kinasesrc. Src and PTPs control signaling in the PI3K-Akt survival pathway. DSPs and ASK1 are important regulators of ERK1/2, p38 and JNK mitogen activated kinase (MAPK) pathways, which are important for a number of functions including survival, apoptosis, inflammation and stress responses. NOX enzymes have also been shown to regulate intracellular or plasma membrane ion channels. RTK= receptor tyrosin kinase, CR= cytokine receptor.

Fig.3 The roles of NOX in neurodegenerative disease. NOX enzymes are expressed in neurons, astrocytes and microglia. Over-activation of NOX in neurons can lead to neuronal damage and release of injury signals which activatesurrounding astrocytes and microglia. Activated astrocytes and microglia in turn upregulate their NOX activity resulting in release of ROS and further oxidative damage to neurons. Chronic activation of NOX in microglia can also result in microglial priming and release of additional neurotoxic molecules. In astrocytes, the ROS can damage glutamate transporters resulting in decreased clearance of glutamate from the synaptic cleft. This in turn can result in over-activation of NMDA receptors, increased NOX activationand excitotoxicity in neurons. Excitotoxicity results in increased Ca levels, mitochondrial damage and increased mitochondrial ROS production in the neuron.

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