Neuronal NADPH oxidase in Parkinson disease pathogenesis
Keeney, M. T.; Hoffman, E. K.; Farmer, K.; Bodle, C. R.; Fazzari, M.; Zharikov, A.; Castro, S. L.; Kofler, J. K.; Cifuentes-Pagano, E.; Pagano, P. J.; Burton, E. A.; Hastings, T. G.; Greenamyre, J. T.; Di Maio, R.
Show abstract
Mitochondrial dysfunction and oxidative stress are strongly implicated in the pathogenesis of Parkinsons disease (PD) and there is evidence that mitochondrially-generated superoxide can activate NADPH oxidase 2 (NOX2), which is a major enzymatic generator of superoxide. Although NOX2 has been examined in the context of PD, previous studies have focused on microglial function; the role of neuronal NOX2 in PD pathogenesis remains to be defined. Here we devised and validated a proximity ligation assay for NOX2 activity and demonstrated that in human PD and 2 models thereof, neuronal NOX2 is highly active in substantia nigra dopamine neurons. Further, NOX2 activity is responsible for accumulation, post-translational modification and oligomerization of -synuclein as well as activation of leucine-rich repeat kinase 2 (LRRK2). Administration of a brain-penetrant, specific NOX2 inhibitor prevented NOX2 activation and its downstream effects in vivo in a rat model of PD. We conclude that neuronal NOX2 is a major contributor to oxidative stress in PD, to -synuclein pathology and to LRRK2 activation in idiopathic PD. In this context, NOX2 inhibitors hold potential as a disease-modifying therapy in PD. SummaryIn dopamine neuron, NADPH oxidase isoform 2 amplifies the oxidative stress-related pathogenic cascade in Parkinsons disease
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