Oxidative Stress in DNA Repeat Expansion Disorders: A Focus on NRF2 Signaling Involvement

Abstract

DNA repeat expansion disorders are a group of neuromuscular and neurodegenerative diseases that arise from the inheritance of long tracts of nucleotide repetitions, located in the regulatory region, introns, or inside the coding sequence of a gene. Although loss of protein expression and/or the gain of function of its transcribed mRNA or translated product represent the major pathogenic effect of these pathologies, mitochondrial dysfunction and imbalance in redox homeostasis are reported as common features in these disorders, deeply affecting their severity and progression. In this review, we examine the role that the redox imbalance plays in the pathological mechanisms of DNA expansion disorders and the recent advances on antioxidant treatments, particularly focusing on the expression and the activity of the transcription factor NRF2, the main cellular regulator of the antioxidant response.

Keywords: DNA repeat expansion disorders; FXTAS; Friedreich’s ataxia; Huntington’s disease; NRF2; fragile X syndrome; myotonic dystrophy; oxidative stress; spinal and bulbar muscular atrophy; spinocerebellar ataxia.

Figure 1

Putative location and sequence of DNA expansions in repeat disorders. Schematic representation of an ideal gene showing DNA repeat expansions that cause diseases. Name of the relative disorder, number of pathogenic repeats, and its sequence are reported in the gene region were the repeats stem in the pathology. The grey arrow represents pathology where oxidative stress has been poorly investigated. Blue arrows characterize diseases with oxidative stress contributions. Red arrows identify pathologies in which NF-E2 p45-related factor 2 (NRF2) involvement has been reported. (FXTAS, fragile X–associated tremor ataxia syndrome; FXS, fragile X syndrome; FA, Friedreich’s ataxia; DM1/DM2 myotonic dystrophy; HD, Huntington’s disease; SCAs, spinocerebellar ataxias; SBMA, spinobulbar muscular atrophy).

Figure 2

Representative model of the NRF2 signaling pathway activation in Friedreich’s Ataxia (FA), based on literature evidences. NRF2 inducers determine the activation of antioxidant genes transcription and the upregulation of enzymes involved in the regulation of glutathione (GSH) expression, rebalancing the unpaired GSH/GSSG ratio and reducing oxidative stress and lipid peroxidation. Importantly, NRF2 also increases frataxin (FXN) levels, thus partially rescuing the mitochondrial defects observed in FA pathology.

Figure 3

Representative model of the NRF2 signaling pathway activation in spinocerebellar ataxia 3 (SCA3), based on literature evidences. As a consequence of NRF2-mediated activation of the antioxidant response, reduction of cellular and mitochondrial ROS production is observed, thus inactivating the apoptotic pathway. In addition, NRF2 increases cellular levels of p62, which shuttles the mutant ataxin 3 aggregates to the autophagosomes, reducing their cellular concentration. At the same time, p62 interferes with the KEAP-1/NRF2 complexes, thus blocking the KEAP-1 mediated NRF2 degradation and sustaining its activity.

Figure 4

Representative model of the NRF2 signaling pathway activation in myotonic dystrophy 1 (DM1), based on literature evidences. Brain-derived neurotrophic factor (BDNF) activation of PI3K/AKT pathway determines the inhibitory phosphorylation of GSK3β by blocking NRF2/KEAP-1-indipendent degradation. As BDNF is a NRF2 target, this can start a positive feedback contributing to NRF2 activation. At the same time, the transcription of NRF2 antioxidant target genes reduces oxidative stress in DM1 cells and the pro-inflammatory cytokine IL-1β levels.