Nicotinamide Adenine Dinucleotide Phosphate Oxidases Are Everywhere in Brain Disease, but Not in Huntington’s Disease?

Abstract

Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by neuronal loss and tissue atrophy mainly in the striatum and cortex. In the early stages of the disease, impairment of neuronal function, synaptic dysfunction and white matter loss precedes neuronal death itself. Relative to other neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease and Amyotrophic Lateral Sclerosis, where the effects of either microglia or NADPH oxidases (NOXs) are recognized as important contributors to disease pathogenesis and progression, there is a pronounced lack of information in HD. This information void contrasts with evidence from human HD patients where blood monocytes and microglia are activated well before HD clinical symptoms (PET scans), and the clear signs of oxidative stress and inflammation in post mortem HD brain. Habitually, NOX activity and oxidative stress in the central nervous system (CNS) are equated with microglia, but research of the last two decades has carved out important roles for NOX enzyme function in neurons. Here, we will convey recent information about the function of NOX enzymes in neurons, and contemplate on putative roles of neuronal NOX in HD. We will focus on NOX-produced reactive oxygen species (ROS) as redox signaling molecules in/among neurons, and the specific roles of NOXs in important processes such as neurogenesis and lineage specification, neurite outgrowth and growth cone dynamics, and synaptic plasticity where NMDAR-dependent signaling, and long-term depression/potentiation are redox-regulated phenomena. HD animal models and induced pluripotent stem cell (iPSC) studies have made it clear that the very same physiological processes are also affected in HD, and we will speculate on possible roles for NOX in the pathogenesis and development of disease. Finally, we also take into account the limited information on microglia in HD and relate this to any contribution of NOX enzymes.

NADPH-oxidases as potential pharmacological targets for thrombosis and depression comorbidity

“…NOX2 activation involve the interactions of different proteins, beginning with phosphorylation of the cytosolic p47 phox /p67 phox complex, which in turn causes a conformational shift that facilitates the interaction with the p22 phox subunit. After the complex is translocated into the membrane, p67 phox bind to NOX2 and recruits the p40 phox and GTPase Rac subunits, which modulate NOX2 activity [ [110] , [111] , [112] , [113] ]. After the complex is assembled, it becomes active and produces by transferring electrons from cytosolic NADPH to oxygen in the extracellular or luminal region.…”

“…NOX3 similarly interacts with p22 phox and NOXO1, whereas NOX4 is constitutively active and exclusively linked with p22 phox . Activation of NOX5 and DUOX1/2 is modulated by a calcium-calmodulin-binding protein or directly by Ca 2+ [ 110 , 111 , [113] , [114] , [115] ].…”

“…At the neuronal subcellular level, NOX2, p47 phox , and p22 phox have been localized in the soma, neurites, and synapses, respectively, whereas the exact neuronal distribution of the other NOX subunits has not yet been analyzed in detail [ 113 ].…”

Oxidative Stress in Age-Related Neurodegenerative Diseases: An Overview of Recent Tools and Findings

“…HD is an autosomal dominant neurodegenerative disorder caused by CAG triplet expansions in the Huntingtin gene, encoding an elongated poly-glutamine stretch in the Huntingtin protein. Patients with HD exhibit motor, psychiatric and cognitive deterioration and oxidative stress, although it is not clear whether it is the cause or the consequence of disease progression [105]. Ellederová and co-workers found higher oxidative stress in fibroblasts from a minipig model of HD, compared with wild-type minipig fibroblasts.…”