3. Role of NADPH-Oxidase-Derived ROS Signaling in PD
Epidemiological studies suggest that inflammation increases the risk of developing PD [42]. Several studies revealed that a significant source of ROS generated during inflammation was by NADPH oxidase. Nervous system cells contain the NADPH oxidase complex, which, when assembled and activated, produces free radicals in abundance that can lead to tissue damage [43]. NADPH oxidase which is composed of gp91phox, p67phox, p47phox, p40phox, and p22phox subunits was first studied because of its essential role in host defense [44]. In resting brain cells, NADPH oxidase is inactive because p47phox, p67phox, and p40phox, which are present in the cytosol as a complex, are separated from gp91phox and p22phox, which are transmembrane proteins. Upon activation, the p47phox subunit gets phosphorylated and translocates to the membrane as a complex to assemble with gp91phox and p22phox to form an active NADPH oxidase capable of reducing oxygen to a superoxide radical (O2 −) to generate microglial and/or extramitochondrial-derived ROS [45–48].
Brain regions that are rich in catecholamines, such as adrenaline, noradrenaline, and dopamine, are also exceptionally vulnerable to free radical generation. Catecholamines can spontaneously break down to free radicals or be metabolized to free radicals by endogenous enzymes such as monoamine oxidases. Activated microglia also contribute to the degeneration of dopaminergic neurons by releasing neurotoxic factors such as NADPH-oxidase-derived superoxide and cytokines [49]. Activated microglia can produce a host of toxic molecules including reactive nitrogen species and ROS. Microglia in the vicinity of dopaminergic neurons in disease appears to have an upregulated capacity for ROS production due to increased expression of NADPH oxidase. Release of aggregated and nitrated α-synuclein from dying or damaged dopaminergic neurons in the SN is thought to contribute, in part, to their activation [50, 51].
Additionally, neurons in the vicinity of activated microglia may thus be exposed to NADPH-oxidase-derived O2 − and other secondary oxidants, such as H2O2. NADPH oxidase can be quickly activated to elevate the level of ROS within a few minutes after stimulation by a variety of growth factors, such as cytokines and hormones including interleukin (IL)-1 [52], platelet-derived growth factor (PDGF) [53], or nerve growth factor (NGF) [54].
Several studies indicated that NADPH oxidase has been linked to microglia-derived oxidative stress from a variety of neurotoxic insults, such as rotenone [55], diesel exhaust particles [56], α-synuclein [50], amyloid beta [57], paraquat [58], dopamine neuronal injury [13, 59], and cerebral ischemia-reperfusion injury [60], indicating that microglial NADPH oxidase activation may also be a common denominator of microglial activation associated with neurotoxicity.