Blood‐Based Lipid Peroxidation and Ferroptosis‐Related Markers in Friedreich's Ataxia

BACKGROUND: Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by reduced levels the mitochondrial frataxin protein. Systemic oxidative stress and iron-dependent lipid peroxidation, commonly associated with ferroptosis, have a critical role in disease pathogenesis. OBJECTIVES: We aimed to evaluate longitudinal changes of blood-based indexes of oxidative stress and ferroptosis-related molecules in adults and children with FRDA. METHODS: We measured plasma levels of 4-hydroxyl-2-nonenals (4-HNE) and hydroxyeicosatetraenoic acid (15-HETE), and blood concentration of glutathione (GSH), glutathione disulfide (GSSG), in 62 FRDA patients (48 adults and 14 children) and 63 age matched healthy controls. mRNA levels of major genes targeting the nuclear factor erythroid 2-related factor 2 (NRF2) were also evaluated. Peripheral concentrations of lipid peroxidation markers and ferroptosis-related molecules were correlated with age, disease duration, and severity of ataxia signs. Clinical and biochemical evaluations were performed at baseline and at 1-year follow-up. RESULTS: FRDA patients had significantly increased levels of 4-HNE and GSSG and decreased levels of GSH, compared to controls. Children with FRDA had lower levels of glutathione peroxidase 4 (GPX4) mRNA than adult patients. At 1-year follow up, plasma 4-HNE levels remained stable, and blood GPX4 mRNA increased only in adult patient cohort. GPX4 correlated with age, disease duration, and clinical scores. CONCLUSIONS: We provide preliminary evidence of defective GPX4 expression in the early phase of the disease. Our data suggest that GPX4 may represent a biomarker for disease progression and a possible candidate target for therapeutic strategies.