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Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study

Friedreich’s ataxia (FRDA) is the most frequent autosomal recessive ataxia in western countries, with a mean age of onset at 10–15 years. Patients manifest progressive cerebellar and sensory ataxia, dysarthria, lower limb pyramidal weakness, and other systemic manifestations. Previously, we describe...

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Autores principales: Petrillo, Sara, Santoro, Massimo, La Rosa, Piergiorgio, Perna, Alessia, Gallo, Maria Giovanna, Bertini, Enrico Silvio, Silvestri, Gabriella, Piemonte, Fiorella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940825/
https://www.ncbi.nlm.nih.gov/pubmed/33708070
http://dx.doi.org/10.3389/fnins.2021.638810
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author Petrillo, Sara
Santoro, Massimo
La Rosa, Piergiorgio
Perna, Alessia
Gallo, Maria Giovanna
Bertini, Enrico Silvio
Silvestri, Gabriella
Piemonte, Fiorella
author_facet Petrillo, Sara
Santoro, Massimo
La Rosa, Piergiorgio
Perna, Alessia
Gallo, Maria Giovanna
Bertini, Enrico Silvio
Silvestri, Gabriella
Piemonte, Fiorella
author_sort Petrillo, Sara
collection PubMed
description Friedreich’s ataxia (FRDA) is the most frequent autosomal recessive ataxia in western countries, with a mean age of onset at 10–15 years. Patients manifest progressive cerebellar and sensory ataxia, dysarthria, lower limb pyramidal weakness, and other systemic manifestations. Previously, we described a family displaying two expanded GAA alleles not only in the proband affected by late-onset FRDA but also in the two asymptomatic family members: the mother and the younger sister. Both of them showed a significant reduction of frataxin levels, without any disease manifestation. Here, we analyzed if a protective mechanism might contribute to modulate the phenotype in this family. We particularly focused on the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), the first line of antioxidant defense in cells, and on the glutathione (GSH) system, an index of reactive oxygen species (ROS) detoxification ability. Our findings show a great reactivity of the GSH system to the frataxin deficiency, particularly in the asymptomatic mother, where the genes of GSH synthesis [glutamate–cysteine ligase (GCL)] and GSSG detoxification [GSH S-reductase (GSR)] were highly responsive. The GSR was activated even in the asymptomatic sister and in the proband, reflecting the need of buffering the GSSG increase. Furthermore, and contrasting the NRF2 expression documented in FRDA tissues, NRF2 was highly activated in the mother and in the younger sister, while it was constitutively low in the proband. This suggests that, also under frataxin depletion, the endogenous stimulation of NRF2 in asymptomatic FRDA subjects may contribute to protect against the progressive oxidative damage, helping to prevent the onset of neurological symptoms and highlighting an “out-brain origin” of the disease.
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spelling pubmed-79408252021-03-10 Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study Petrillo, Sara Santoro, Massimo La Rosa, Piergiorgio Perna, Alessia Gallo, Maria Giovanna Bertini, Enrico Silvio Silvestri, Gabriella Piemonte, Fiorella Front Neurosci Neuroscience Friedreich’s ataxia (FRDA) is the most frequent autosomal recessive ataxia in western countries, with a mean age of onset at 10–15 years. Patients manifest progressive cerebellar and sensory ataxia, dysarthria, lower limb pyramidal weakness, and other systemic manifestations. Previously, we described a family displaying two expanded GAA alleles not only in the proband affected by late-onset FRDA but also in the two asymptomatic family members: the mother and the younger sister. Both of them showed a significant reduction of frataxin levels, without any disease manifestation. Here, we analyzed if a protective mechanism might contribute to modulate the phenotype in this family. We particularly focused on the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), the first line of antioxidant defense in cells, and on the glutathione (GSH) system, an index of reactive oxygen species (ROS) detoxification ability. Our findings show a great reactivity of the GSH system to the frataxin deficiency, particularly in the asymptomatic mother, where the genes of GSH synthesis [glutamate–cysteine ligase (GCL)] and GSSG detoxification [GSH S-reductase (GSR)] were highly responsive. The GSR was activated even in the asymptomatic sister and in the proband, reflecting the need of buffering the GSSG increase. Furthermore, and contrasting the NRF2 expression documented in FRDA tissues, NRF2 was highly activated in the mother and in the younger sister, while it was constitutively low in the proband. This suggests that, also under frataxin depletion, the endogenous stimulation of NRF2 in asymptomatic FRDA subjects may contribute to protect against the progressive oxidative damage, helping to prevent the onset of neurological symptoms and highlighting an “out-brain origin” of the disease. Frontiers Media S.A. 2021-02-23 /pmc/articles/PMC7940825/ /pubmed/33708070 http://dx.doi.org/10.3389/fnins.2021.638810 Text en Copyright © 2021 Petrillo, Santoro, La Rosa, Perna, Gallo, Bertini, Silvestri and Piemonte. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Petrillo, Sara
Santoro, Massimo
La Rosa, Piergiorgio
Perna, Alessia
Gallo, Maria Giovanna
Bertini, Enrico Silvio
Silvestri, Gabriella
Piemonte, Fiorella
Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study
title Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study
title_full Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study
title_fullStr Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study
title_full_unstemmed Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study
title_short Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study
title_sort nuclear factor erythroid 2-related factor 2 activation might mitigate clinical symptoms in friedreich’s ataxia: clues of an “out-brain origin” of the disease from a family study
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940825/
https://www.ncbi.nlm.nih.gov/pubmed/33708070
http://dx.doi.org/10.3389/fnins.2021.638810
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