Adding a temporal dimension to the study of Friedreich's ataxia: the effect of frataxin overexpression in a human cell model

作者：Vannocci Tommaso; Manzano Roberto Notario; Beccalli Ombretta; Bettegazzi Barbara; Grohovaz Fabio; Cinque Gianfelice; de Riso Antonio; Quaroni Luca; Codazzi Franca; Pastore Annalisa^*

来源：Disease Models & Mechanisms, 2018, 11(6): UNSP dmm032706.

DOI：10.1242/dmm.032706

• Frataxin
• Friedreich's ataxia
• Overexpression
• Oxidative stress

The neurodegenerative disease Friedreich's ataxia is caused by lower than normal levels of frataxin, an important protein involved in iron-sulfur (Fe-S) cluster biogenesis. An important step in designing strategies to treat this disease is to understand whether increasing the frataxin levels by gene therapy would simply be beneficial or detrimental, because previous studies, mostly based on animal models, have reported conflicting results. Here, we have exploited an inducible model, which we developed using the CRISPR/Cas9 methodology, to study the effects of frataxin overexpression in human cells and monitor how the system recovers after overexpression. Using new tools, which range from high-throughput microscopy to in cell infrared, we prove that overexpression of the frataxin gene affects the cellular metabolism. It also leads to a significant increase of oxidative stress and labile iron pool levels. These cellular alterations are similar to those observed when the gene is partly silenced, as occurs in Friedreich's ataxia patients. Our data suggest that the levels of frataxin must be tightly regulated and fine-tuned, with any imbalance leading to oxidative stress and toxicity.

• 出版日期2018-6