Friedreich's ataxia (FRDA) is a trinucleotide repeat expansion neurodegenerative disorder, in which GAA repeats in the first intron of FXN gene, abolish the expression of frataxin. Although congenital, this defect triggers the onset of the pathology predominantly in the second decade of life. One of the main events landmarking the pathologic onset of the disease is the death of dorsal root ganglia (DRG) neurons. However, cognitive defects in FRDA patients point to neurodevelopmental, pre-symptomatic impairments that occur largely before the overt manifestation of symptoms. At cellular level, frataxin deficiency impairs heme- and iron-sulphur cluster-containing protein biosynthesis, causing dysfunction in the respiratory electron transport chain and mitochondrial iron accumulation. This leads to an increase of the oxidative stress and membrane lipid peroxidation, and impairs the antioxidant response, by altering the proper localization and expression of the NF-E2 p45-related factor 2 (NRF2), the master regulator of antioxidant defence. These defects are markers of a recently described type of cell death, known as ferroptosis. We hypothesize that the progressive accumulation of oxidative stress-induced damage in early life triggers this cellular pathway, unleashing the pathologic onset. To investigate this possibility, we propose: (i) to characterize the defects that take place during the cortical development in the Frataxin Knockin/Knockout (KIKO) mouse; (ii) to unveil the molecular determinants that trigger these defects, through a high-throughput approach and to evaluate if re-establishing the cellular antioxidant defence we are able to rescue these defects; (iii) to determine how and when the accumulation of frataxin depletion-induced impairments causes the uprising of ferroptotic markers in the DRG of YG8R mice and if these markers can be traced in the blood of FRDA patients, to be exploited as reliable biomarkers and new therapeutic targets of the pathology.
