AUTHOR=Petrillo Sara , Santoro Massimo , La Rosa Piergiorgio , Perna Alessia , Gallo Maria Giovanna , Bertini Enrico Silvio , Silvestri Gabriella , Piemonte Fiorella 

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

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 15 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.638810

DOI=10.3389/fnins.2021.638810

ISSN=1662-453X

ABSTRACT=Friedreich ataxia (FRDA) is the most frequent autosomal recessive ataxia in western countries. Patients manifest symptoms before age 25, with progressive cerebellar and sensory ataxia, dysarthria, lower limbs 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 Friedreich’s ataxia, 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 analysed if a protective mechanism might contribute to modulate the phenotype in this family. We particularly focused on the transcription factor NRF2, the first line of antioxidant defence in cells, and on the glutathione system, an index of ROS detoxification ability. 
Our findings show a great reactivity of the glutathione system to the frataxin deficiency, particularly in the asymptomatic mother, where the genes of GSH synthesis (GCL) and GSSG detoxification (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, suggesting that the endogenous stimulation of NRF2 in the asymptomatic subjects may contribute to protect against the progressive oxidative damage and help to prevent the onset of symptoms in FRDA, also under frataxin depletion.