The NRF2 signaling network defines clinical biomarkers and therapeutic opportunity in Friedreich’s Ataxia: International Journal of Molecular Sciences

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Friedreich’s ataxia (FA) is a trinucleotide repeats expansion neurodegenerative disorder, for which no cure or approved therapies are present. In most cases, GAA trinucleotide repetitions in the first intron of the FXN gene are the genetic trigger of FA, determining a strong reduction of frataxin, a mitochondrial protein involved in iron homeostasis. Frataxin depletion impairs iron– sulfur cluster biosynthesis and determines iron accumulation in the mitochondria. Mounting evidence suggests that these defects increase oxidative stress susceptibility and reactive oxygen species production in FA, where the pathologic picture is worsened by a defective regulation of the expression and signaling pathway modulation of the transcription factor NF-E2 p45-related factor 2 (NRF2), one of the fundamental mediators of the cellular antioxidant response. NRF2 protein downregulation and impairment of its nuclear translocation can compromise the adequate cellular response to the frataxin depletion-dependent redox imbalance. As NRF2 stability, expression, and activation can be modulated by diverse natural and synthetic compounds, efforts have been made in recent years to understand if regulating NRF2 signaling might ameliorate the pathologic defects in FA. Here we provide an analysis of the pharmaceutical interventions aimed at restoring the NRF2 signaling network in FA, elucidating specific biomarkers useful for monitoring therapeutic effectiveness, and developing new therapeutic tools. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Original languageEnglish
JournalInt. J. Mol. Sci.
Issue number3
Publication statusPublished - 2020


  • Frataxin
  • Friedreich’s ataxia
  • Neurodegenerative diseases
  • NRF2
  • Redox active drugs
  • creatine kinase MM
  • cullin
  • cysteine synthase
  • glutathione synthase
  • histone deacetylase
  • kelch like ECH associated protein 1
  • mitochondrial protein
  • transcription factor Maf
  • transcription factor NF E2 p45 subunit
  • transcription factor Nrf2
  • biological marker
  • NFE2L2 protein, human
  • antioxidant activity
  • biosynthesis
  • cell migration
  • degenerative disease
  • down regulation
  • enzyme activity
  • Friedreich ataxia
  • gene control
  • gene expression
  • genetic analysis
  • genetic transcription
  • human
  • lipid peroxidation
  • mitochondrial biogenesis
  • molecular recognition
  • oxidative stress
  • protein phosphorylation
  • Review
  • signal transduction
  • metabolism
  • Biomarkers
  • Friedreich Ataxia
  • Humans
  • NF-E2-Related Factor 2
  • Signal Transduction


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