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\r\ncountries, with a mean age of onset at 10–15 years. Patients manifest progressive\r\ncerebellar and sensory ataxia, dysarthria, lower limb pyramidal weakness, and other\r\nsystemic manifestations. Previously, we described a family displaying two expanded\r\nGAA alleles not only in the proband affected by late-onset FRDA but also in the two\r\nasymptomatic family members: the mother and the younger sister. Both of them showed\r\na significant reduction of frataxin levels, without any disease manifestation. Here, we\r\nanalyzed if a protective mechanism might contribute to modulate the phenotype in this\r\nfamily. We particularly focused on the transcription factor nuclear factor erythroid 2-\r\nrelated factor 2 (NRF2), the first line of antioxidant defense in cells, and on the glutathione\r\n(GSH) system, an index of reactive oxygen species (ROS) detoxification ability. Our\r\nfindings show a great reactivity of the GSH system to the frataxin deficiency, particularly\r\nin the asymptomatic mother, where the genes of GSH synthesis [glutamate–cysteine\r\nligase (GCL)] and GSSG detoxification [GSH S-reductase (GSR)] were highly responsive.\r\nThe GSR was activated even in the asymptomatic sister and in the proband, reflecting\r\nthe need of buffering the GSSG increase. Furthermore, and contrasting the NRF2\r\nexpression documented in FRDA tissues, NRF2 was highly activated in the mother and\r\nin the younger sister, while it was constitutively low in the proband. This suggests that,\r\nalso under frataxin depletion, the endogenous stimulation of NRF2 in asymptomatic\r\nFRDA subjects may contribute to protect against the progressive oxidative damage,\r\nhelping to prevent the onset of neurological symptoms and highlighting an “out-brain\r\norigin” of the disease.