One-to-one Benefit provided by Antioxidants to cultured skin Fibroblasts from Friedreich Ataxia patients

Abstract

With the hope of better understanding and characterizing the dramatic differences in antioxidant response of human cells carrying mutations in the frataxin gene responsible for Friedreich ataxia (FRDA), we studied primary cultures of skin fibroblasts derived from five FRDA patients harboring different large expansion sizes in the frataxin gene. Because oxidative stress was previously established to be instrumental in FRDA, among the many enzymes likely to modulate sensitivity to oxidative stress, we selected some previously shown to play a critical role in this stress. However, we failed to identify a consistent clue to order individual cultures based on these measurements. We therefore focused our study on cell death of FRDA fibroblasts and its modulation by different antioxidants under culture conditions exacerbating sensitivity to oxidative stress. Under conditions that force the cells to rely on mitochondrial activity, we observed significant yet variable FRDA cell proliferation. These conditions were thereafter used to screen the effectiveness of a set of antioxidant molecules targeting different steps of the pro-oxidant cascade previously documented in FRDA, i.e. Uridine, Pyruvate, and Pioglitazone, to prevent or slow down cell mortality. We observed a surprising variability of response to antioxidant molecules even under the similar, controlled conditions used to culture patients fibroblasts. We conclude that the specific response of each individual already discernable at cellular level may well play an important role in the frequent difficulties encounter to reach firm conclusions when testing the capacity of antioxidants to counteract the consequences of frataxin depletion, including in clinical trials.