NADPH oxidases: novel therapeutic targets for neurodegenerative diseases

Abstract

Oxidative stress is a key pathologic factor in neurodegenerative diseases such as Alzheimer and Parkinson diseases (AD, PD). The failure of free-radical-scavenging antioxidants in clinical trials pinpoints an urgent need to identify and to block major sources of oxidative stress in neurodegenerative diseases. As a major superoxide-producing enzyme complex in activated phagocytes, phagocyte NADPH oxidase (PHOX) is essential for host defense. However, recent preclinical evidence has underscored a pivotal role of overactivated PHOX in chronic neuroinflammation and progressive neurodegeneration. Deficiency in PHOX subunits mitigates neuronal damage induced by diverse insults/stresses relevant to neurodegenerative diseases. More importantly, suppression of PHOX activity correlates with reduced neuronal impairment in models of neurodegenerative diseases. The discovery of PHOX and non-phagocyte NADPH oxidases in astroglia and neurons further reinforces the crucial role of NADPH oxidases in oxidative stress-mediated chronic neurodegeneration. Thus, proper modulation of NADPH oxidase activity might hold therapeutic potential for currently incurable neurodegenerative diseases.

Figure 1. The coupling between Mac1 and PHOX in microglia-mediated ROS production

Microglia as the resident immune cells in the CNS can sense subtle disturbances of CNS homeostasis. The phagocyte NADPH oxidase (PHOX) is dormant in resting microglia and separated into individual cytosolic and membrane-bound components. A variety of stimuli, such as chemotactic peptides can stimulate microglia an d induce PHOX activation. In particular, some cellular components (e.g. HMGB1, α-synuclein, and β-amyloid) released from activated microglia and/ or damaged neurons can act on microglial Mac1 receptor and activate downstream kinases (e.g. PI3K) leading to the phosphorylation of cytosolic subunits of PHOX, p47^phox and p67^phox; subsequent translocation of the cytosolic complex composed of p47^phox, p67^phox, p40^phox, and Rac2 to the membrane-bound p22^phox/ NOX2 heterodimer results in the assembly of an active PHOX. The activated NOX2 transfers electrons across the plasma membrane from NADPH to molecular oxygen and generates the free-radical superoxide. The coupling between Mac1 and PHOX represents an important mechanism underlying microgliamediated NOX2-dependent oxidative insults to neurons in the progression of neurodegenerative d iseases.

Figure 2. NOX2-derived ROS from activated microglia mediate chronic oxidative neuronal damage in neurodegenerative diseases

NOX2-derived oxidants from activated microglia, such as H₂O₂ (non-radical oxidants) and peroxynitrite (a reactive product of superoxide and nitric oxide) can enter neurons and lead to 1) mitochondrial impairment and dysfunction, reduced ATP production, and increased generation of mitochondria-derived free radicals; 2) protein oxidation, nitration, aggregation, and accumulation; 3) dysfunction of the ubiquitin-proteasome system (UPS) and reduced protein degradation; 4) impaired redox-sensitive signal transduction; 5) oxidation of DNA, RNA, and lipids; and 6) ROS-induced autophagy. All these oxidative damages of neurons are integral components of chronic neurodegenerative process.