The Nrf2-ARE pathway: A potential therapeutic target for neurodegenerative diseases

Abstract

NF-E2-related factor 2 (Nrf2) is the primary transcription factor required for the induction of a battery of phase II detoxification genes through activation of a cis-acting enhance termed the antioxidant response element (ARE). The genes regulated by the Nrf2-ARE pathway respond to and increase resistance to oxidative stress and/or mitochondrial dysfunction. Oxidative stress or mitochondrial dysfunction have been implicated in the pathogenesis of multiple neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's Disease and amyotrophic lateral sclerosis (Lou Gehrig's disease). Both chemical and genetic models of some of these diseases in mice, as well as primary neuronal culture systems, have been used to look at the Nrf2-ARE pathway in regard to neuroprotection. Activation of this pathway protects neurons from toxic insults such as mitochondrial complex I and complex II inhibitors, glutamate, hydrogen peroxide and increased intracellular calcium. Conversely, knockout or knockdown of Nrf2 leads to increased sensitivity of neurons to toxin-induced cell death. Interestingly, this neuroprotective mechanism appears to be manifest through the astrocyte. Selective inhibition of Nrf2 function or overexpression in these non-neuronal cells has dramatic effects on the protective potential of this system. Clearly, a greater understanding of how the Nrf2-ARE pathway is intimately involved with the pathogenesis of neurodegenerative diseases and its significant neuroprotective properties could be pivotal in halting the progression of multiple neurological diseases through the development of new therapeutic approaches targeting this pathway.