One-to-one Benefit Provided by Antioxidants to Cultured Skin Fibroblasts from Friedreich Ataxia Patients

Abstract

As to better understand and characterize the dramatic differences in antioxidant response of human cells harboring mutations in the frataxin gene responsible for Friedreich's ataxia (FRDA), we studied primary cultures of skin fibroblasts derived from five FRDA patients with different major frataxin gene expansion sizes. Since oxidative stress has been previously established to play a critical role in FRDA, among the many enzymes that may modulate oxidative stress sensitivity, we selected some that have previously been shown to be critical in oxidative stress. However, we were unable to identify a consistent index to rank individual cultures based on these measures. We therefore focused our study on FRDA fibroblast cell death and its modulation by different antioxidants under culture conditions that exacerbate oxidative stress sensitivity. Under conditions that require cells to rely on mitochondrial activity, we observed significant but variable effect on FRDA cell proliferation. These conditions were then used to test the efficacy to prevent or slow down cell death, of a panel of antioxidant molecules targeting different steps of the pro-oxidant cascade previously documented in FRDA, namely uridine, pyruvate, and pioglitazone. We observed a surprising variability in the response of patient fibroblasts to antioxidant molecules even using similar culture conditions. We conclude that the individual-specific response already discernible at the cellular level may well play an important role in the frequent difficulties encountered in reaching definitive conclusions when testing the ability of antioxidants to counteract the consequences of frataxin depletion, a conclusion that may apply to clinical trials as well.