Friedreich’s ataxia (FRDA) is a rare monogenic disease characterized by multisystem, slowly progressive degeneration. Because of the genetic defect in a non-coding region of FXN gene, FRDA cells exhibit severe deficit of frataxin protein levels. Hence, FRDA pathophysiology is characterized by a plethora of metabolic disruptions related to iron metabolism, mitochondrial homeostasis and oxidative stress. Importantly, an impairment of the antioxidant defences exacerbates the oxidative damage. This appears closely associated with the disablement of key antioxidant proteins, such as the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and the mitochondrial superoxide dismutase (MnSOD). The cytokine interferon gamma (IFN-γ) has been shown to increase frataxin expression in FRDA cells and to improve functional deficits in FRDA mice. Currently, IFN-γ represents a potential therapy under clinical evaluation in FRDA patients. Here, we show that IFN-γ induces a rapid expression of Nrf2 and MnSOD in different cell types, including FRDA patient-derived fibroblasts. Our data indicate that IFN-γ signals two separate pathways to enhance Nrf2 and MnSOD levels in FRDA fibroblasts. MnSOD expression increased through an early transcriptional regulation, whereas the levels of Nrf2 are induced by a post-transcriptional mechanism. We demonstrate that the treatment of FRDA fibroblasts with IFN-γ stimulates a non-canonical Nrf2 activation pathway through p21 and potentiates antioxidant responses under exposure to hydrogen peroxide. Moreover, IFN-γ significantly reduced the sensitivity to hydrogen peroxide-induced cell death in FRDA fibroblasts. Collectively, these results indicate the presence of multiple pathways triggered by IFN-γ with therapeutic relevance to FRDA.

Friedreich ataxia (FRDA) is the most common inherited ataxia, primarily impacting the nervous system and the heart. It is characterized by GAA repeat expansion in the FXN gene, leading to reduced mitochondrial frataxin levels. Previously, we described a family displaying two expanded GAA alleles, not only in the proband affected by late-onset FRDA but also in the younger asymptomatic sister. The molecular characterization of the expanded repeats showed that the affected sister carried two canonical uninterrupted GAA expended repeats, whereas the asymptomatic sister had a compound heterozygous for a canonical GAA repeat and an expanded GAAGGA motif. Therefore, we decided to perform RNA sequencing (RNA-seq) on fibroblasts from both sisters in order to understand whether some genes and/or pathways might be differently involved in the occurrence of FRDA clinical manifestation. The transcriptomic analysis revealed 398 differentially expressed genes. Notably, TLR4, IL20RB, and SLITRK5 were up-regulated, while TCF21 and GRIN2A were down-regulated, as validated by qRT-PCR. Gene ontology (GO) enrichment and network analysis highlighted significant involvement in immune response and neuronal functions. Our results, in particular, suggest that TLR4 may contribute to inflammation in FRDA, while IL20RB, SLITRK5, TCF21, and GRIN2A dysregulation may play roles in the disease pathogenesis. This study introduces new perspectives on the inflammatory and developmental aspects in FRDA, offering potential targets for therapeutic intervention.

Background/Objectives: The COVID-19 pandemic has caused sickness and death among many health care workers. However, the apparent resistance of health care workers to SARS-CoV-2 infection despite their high-risk work environment remains unclear. To investigate if inflammation and circadian disruption contribute to resistance or diminished susceptibility to the SARS-CoV-2 virus, we retrospectively evaluated a cohort of volunteer hospital nurses (VHNs). Methods: A total of 246 apparently healthy VHNs (mean age 37.4 ± 5.9 years) who had received the BNT162b2 mRNA vaccine were asked to report their sleep quality, according to the Pittsburgh Sleep Quality Index, and number of SARS-CoV-2 infections during the observational study period (from the end of December 2020 to April 2025). The expression of inflammation-associated mediators and circadian transcription factors in peripheral blood mononuclear cells, as well as sleep quality, were examined. Results: Our findings revealed no anthropometric, biochemical, or inflammation-associated parameters but demonstrated significantly greater levels of NFE2L2, also known as nuclear factor erythroid-derived 2-like 2 (NFR2), gene expression in peripheral blood mononuclear cells among VHNs who had never been infected with SARS-CoV-2 (n = 97) than in VHNs with only one (n = 119) or with two or more (n = 35) prior SARS-CoV-2 infections (p < 0.01). This result was confirmed through one-to-one propensity score matching (p < 0.01). Moreover, NRF2 gene expression was not associated with the number of COVID-19 vaccinations (p = 0.598). Finally, NRF2 gene expression was higher among participants who reported better sleep quality (p < 0.01). Conclusions: Our findings suggest possible interactions among NRF2 gene expression, protection against SARS-CoV-2 infection, and the modulation of COVID-19 vaccination efficacy.