The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich's Ataxia.
Int J Mol Sci
; 21(3)2020 01 30.
Article
em En
| MEDLINE
| ID: mdl-32019240
ABSTRACT
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ataxia de Friedreich
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Biomarcadores
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Fator 2 Relacionado a NF-E2
Limite:
Humans
Idioma:
En
Revista:
Int J Mol Sci
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Itália