In Vitro Assessment of the Radiosensitivity of Friedreich’s Ataxia Fibroblasts

Abstract

Introduction: Friedreich’s Ataxia (FRDA) is a neurodegenerative disorder that stands as the most common form of inherited ataxia. FRDA affects 15,000 individuals worldwide, with approximately 250 documented cases in Lebanon. FRDA is an autosomal recessive disorder caused by a GAA triplet expansion on the FXN gene, that encodes for the protein Frataxin. The onset of symptoms typically manifests in childhood or early adolescence, Rare studies have shown that individuals with FRDA have an increased radiosensitivity compared to the normal population. In fact, radiation or exposure to any genotoxic stress induces different types of DNA damage, with double-strand breaks (DSBs) being the most lethal. Recent advancements in radiobiology have highlighted the importance of assessing the kinetics of the DSBs damage and repair pathway proteins in assessing radiosensitivity.

Aim: To assess the in vitro radiosensitivity of FRDA fibroblasts.

Methods: Five human skin fibroblasts (three FRDA and two normal fibroblasts) were used in this study. Cells were exposed to a 2 Gy irradiation, and the DNA DSB signaling and repair pathways were analyzed by anti-pATM and anti-γH2AX immunofluorescence. The clonogenic assay was performed to characterize the cellular radiosensitivity.

Results: FRDA cell lines exhibited an impaired DSB repair mechanism when compared with the normal cell lines. Additionally, the post-irradiation pATM activity was significantly lower in FRDA cell lines than in normal fibroblasts.

Conclusion: Our results show that FRDA cells have a significant radiosensitivity caused by the impairment of their DNA DSB repair mechanism. These findings, if confirmed by other studies, will lead to the modification and development of FRDA treatment strategies that will take into account their increased radiosensitivity.