NADPH oxidases in Parkinson's disease: a systematic review

Abstract

Parkinson's disease (PD) is a progressive movement neurodegenerative disease associated with a loss of dopaminergic neurons in the substantia nigra of the brain. Oxidative stress, a condition that occurs due to imbalance in oxidant and antioxidant status, is thought to play an important role in dopaminergic neurotoxicity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are multi-subunit enzymatic complexes that generate reactive oxygen species as their primary function. Increased immunoreactivities for the NADPH oxidases catalytic subunits Nox1, Nox2 and Nox4 have been reported in the brain of PD patients. Furthermore, knockout or genetic inactivation of NADPH oxidases exert a neuroprotective effect and reduce detrimental aspects of pathology in experimental models of the disease. However, the connections between NADPH oxidases and the biological processes believed to contribute to neuronal death are not well known. This review provides a comprehensive summary of our current understanding about expression and physiological function of NADPH oxidases in neurons, microglia and astrocytes and their pathophysiological roles in PD. It summarizes the findings supporting the role of both microglial and neuronal NADPH oxidases in cellular disturbances associated with PD such as neuroinflammation, alpha-synuclein accumulation, mitochondrial and synaptic dysfunction or disruption of the autophagy-lysosome system. Furthermore, this review highlights different steps that are essential for NADPH oxidases enzymatic activity and pinpoints major obstacles to overcome for the development of effective NADPH oxidases inhibitors for PD.

Keywords: Alpha-synuclein; Microglia; Mitochondria; Neurodegenerative disorders; Oxidative stress; Synaptic plasticity.

Fig. 1

Activation of the NADPH oxidase family members. The figure illustrates for each NADPH oxidase the catalytic core region (in blue), the transmembrane maturation and stabilization subunits (in red) as well as the cytosolic subunits and the small GTPases (Rac1 and Rac2). The predicted regions for FAD and NADPH binding sites and the putative peroxidase-like region are also shown, as well as the EF hand motifs (yellow circles) that bind to Ca²⁺

Fig. 2

Cellular and subcellular expression of NADPH oxidase catalytic subunits in the brain. a Schematic diagram showing the reported cellular localization of NADPH oxidase family members in the brain cells. b Schematic diagram showing the reported subcellular localization of NADPH oxidase family members in a hypothetical cell in the brain

Fig. 3

Alpha-synuclein and microglial Nox2 activation. The activation of microglia by alpha-synuclein can implicate several cell surface receptors such as P2X7, TLR2/4 and CR3 and subsequent activations of several kinases such as PKC, Akt, MAPKs, PAK and ERK1/2. This in turn could promote the phosphorylation and translocation of p47phox and subsequent Nox2 activation. Released oxygen species appear to promote microglia chemoattraction, activation and oxidative stress. Neuronal damage leads to the release of alpha-synuclein and the TLR-agonist high mobility group box protein 1 (HMGB1)

Fig. 4

Proposed role for NADPH oxidases in PD. Schematic view of the link between both microglial and neuronal NADPH oxidases and cellular processes related to PD, e.g. alpha-synuclein signaling, microglia activation, oxidative stress and neuronal damage, mitochondria dysfunction, disruption of the autophagy-lysosome system, synaptic dysfunction and excitotoxicity. Localizations of NADPH oxidases are indicated in grey