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

DOI: 10.1242/dmm.032706 DOI Help

Authors: Tommaso Vannocci (King's College London) , Roberto Notario Manzano (King's College London) , Ombretta Beccalli (Vita-Salute San Raffaele University; IRCCS San Raffaele Scientific Institute) , Barbara Bettegazzi (Vita-Salute San Raffaele University; IRCCS San Raffaele Scientific Institute) , Fabio Grohovaz (Vita-Salute San Raffaele University; IRCCS San Raffaele Scientific Institute) , Gianfelice Cinque (Diamond Light Source) , Antonio De Riso (Hypha Discovery Ltd) , Luca Quaroni (Jagiellonian University) , Franca Codazzi (Vita-Salute San Raffaele University; IRCCS San Raffaele Scientific Institute) , Annalisa Pastore (King's College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Disease Models & Mechanisms

State: Published (Approved)
Published: May 2018
Diamond Proposal Number(s): 5664

Open Access Open Access

Abstract: The neurodegenerative disease Friedreich's ataxia is caused by lower than normal levels of frataxin, an important protein involved in iron sulphur cluster biogenesis. An important step in designing strategies to treat this disease is to understand whether increasing the frataxin levels by gene therapy would be tout-court beneficial or detrimental since 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 follow how the system recovers after overexpression. Using novel 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 lead to a significant increase of oxidative stress and labile iron pool levels. These cellular alterations are similar to those observed when the gene is partially silenced, as it occurs in Friedreich's ataxia's patients. Our data suggest that the levels of frataxin must be tightly regulated and fine-tuned, any imbalance leading to oxidative stress and toxicity.

Journal Keywords: frataxin; Friedreich's ataxia; oxidative stress; overexpression

Subject Areas: Biology and Bio-materials


Instruments: B22-Multimode InfraRed imaging And Microspectroscopy

Documents:
dmm.032706.full.pdf