Nrf2, cellular redox regulation, and neurologic implications

Eduardo E. Benarroch, MD; Neurology May 16, 2017, 88:20 1942-1950; published ahead of print April 19, 2017, 1526-632X  doi: 10.​1212/​WNL.​0000000000003946

Nuclear factor erythroid 2 p45-related factor 2 (Nrf2), encoded by the NFE2L2 gene, is a major regulator of cellular homeostasis. Nrf2 is a transcription factor that promotes the production of components of antioxidant systems, including the glutathione and thiol systems, enzymes of pathways that generate nicotinamide adenine dinucleotide phosphate, and proteins involved in iron metabolism, xenobiotic detoxification, proteostasis, and lipogenesis. Nrf2 protects mitochondrial function and promotes clearance of misfolded proteins, and thus prevents initiation of cell death programs. The regulation and effects of Nrf2 signaling have been reviewed recently. Ntf2 activation is neuroprotective in models of neurologic disorders such as Parkinson disease and multiple sclerosis; impaired Nrf2 signaling may contribute to oxidative stress in Friedreich ataxia. Thus, activation of Nrf2 signaling is an attractive pharmacologic target for neuroprotection. This review focuses on some fundamental aspects of Nrf2 effects on redox systems, mitochondrial function, and proteostasis.