Abstract
Nrf2 is a basic region leucine-zipper transcription factor that plays a pivotal role in the coordinated gene expression of antioxidant and detoxifying enzymes, promoting cell survival in adverse environmental or defective metabolic conditions. After synthesis, Nrf2 is arrested in the cytoplasm by the Kelch-like ECH-associated protein 1 suppressor (Keap1) leading Nrf2 to ubiquitin-dependent degradation. One Nrf2 activation mechanism relies on disconnection from the Keap1 homodimer through the oxidation of cysteine at specific sites of Keap1. Free Nrf2 enters the nucleus, dimerizes with small musculoaponeurotic fibrosarcoma proteins (sMafs), and binds to the antioxidant response element (ARE) sequence of the target genes. Since oxidative stress, next to neuroinflammation and mitochondrial dysfunction, is one of the hallmarks of neurodegenerative pathologies, a molecular intervention into Nrf2/ARE signaling and the enhancement of the transcriptional activity of particular genes are targets for prevention or delaying the onset of age-related and inherited neurogenerative diseases. In this study, we review evidence for the Nrf2/ARE-driven pathway dysfunctions leading to various neurological pathologies, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, as well as amyotrophic lateral sclerosis, and the beneficial role of natural and synthetic molecules that are able to interact with Nrf2 to enhance its protective efficacy.
Highlights
Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is conserved in the metazoan Cap ‘n’ collar (CNC) protein, belonging to the family of basic leucine zippertranscription factors
Nrf2 expression may be upregulated by the breast cancer type 1 susceptibility protein (BRCA1), which functions as a co-activator for the nuclear translocator/aryl hydrocarbon receptor (ARNT/AhR) heterodimer interacting with the xenobiotic response element (XRE)-like sequence in the NFE2L2 [30], or it can act as a direct activator of NFE2L2 [31]
Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disorder caused by a loss of motor neurons in the motor cortex, brain stem, and spinal cord, which subsequently leads to progressive muscle weakness and the loss of voluntary movement control
Summary
Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is conserved in the metazoan Cap ‘n’ collar (CNC) protein, belonging to the family of basic leucine zipper (bZIP). The CNC transcription factors form heterodimers with small musculoaponeurotic fibrosarcoma proteins (sMafs) that either activate or repress the transcription of target genes. The heterodimer Nrf2/sMaf orchestrates the transcription of proteins that collectively favor cell survival through binding to the antioxidant response element (ARE, 50 -(A/G)TGACNNNGC(A/G)-30 ), a cis-acting element of DNA, known as the electrophile response element (EpRE) [2,3,4,5]. This review discusses the molecular regulation of Nrf activity and the contribution of the Nrf2/ARE-driven transcriptional program in most common neurodegenerative diseases. It examines the potential of Nrf activation as a therapeutic target in the treatment of widespread neurological diseases associated with an aging population
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