Adding a temporal dimension to the study of Friedreich's ataxia: the effect of frataxin overexpression in a human cell model
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...
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The Company of Biologists
2018-06-01
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doaj-16551d903a38406a8e868659ead73a772020-11-24T21:46:25ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112018-06-0111610.1242/dmm.032706032706Adding a temporal dimension to the study of Friedreich's ataxia: the effect of frataxin overexpression in a human cell modelTommaso Vannocci0Roberto Notario Manzano1Ombretta Beccalli2Barbara Bettegazzi3Fabio Grohovaz4Gianfelice Cinque5Antonio de Riso6Luca Quaroni7Franca Codazzi8Annalisa Pastore9 Basic and Clinical Neuroscience, Maurice Wohl Institute, King's College London, 5 Cutcombe Road, London SE5 9RT, UK Basic and Clinical Neuroscience, Maurice Wohl Institute, King's College London, 5 Cutcombe Road, London SE5 9RT, UK Division of Neuroscience, Vita-Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy Division of Neuroscience, Vita-Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy Division of Neuroscience, Vita-Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy Department of Physical Chemistry and Electrochemistry, Diamond House, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK Hypha Discovery Ltd, London, UK Department of Physical Chemistry and Electrochemistry, Faculty of Chemistry, Jagiellonian University, PL-30387, Kraków, Poland Division of Neuroscience, Vita-Salute San Raffaele University and IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy Basic and Clinical Neuroscience, Maurice Wohl Institute, King's College London, 5 Cutcombe Road, London SE5 9RT, UK 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.http://dmm.biologists.org/content/11/6/dmm032706FrataxinFriedreich's ataxiaOverexpressionOxidative stress |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tommaso Vannocci Roberto Notario Manzano Ombretta Beccalli Barbara Bettegazzi Fabio Grohovaz Gianfelice Cinque Antonio de Riso Luca Quaroni Franca Codazzi Annalisa Pastore |
spellingShingle |
Tommaso Vannocci Roberto Notario Manzano Ombretta Beccalli Barbara Bettegazzi Fabio Grohovaz Gianfelice Cinque Antonio de Riso Luca Quaroni Franca Codazzi Annalisa Pastore Adding a temporal dimension to the study of Friedreich's ataxia: the effect of frataxin overexpression in a human cell model Disease Models & Mechanisms Frataxin Friedreich's ataxia Overexpression Oxidative stress |
author_facet |
Tommaso Vannocci Roberto Notario Manzano Ombretta Beccalli Barbara Bettegazzi Fabio Grohovaz Gianfelice Cinque Antonio de Riso Luca Quaroni Franca Codazzi Annalisa Pastore |
author_sort |
Tommaso Vannocci |
title |
Adding a temporal dimension to the study of Friedreich's ataxia: the effect of frataxin overexpression in a human cell model |
title_short |
Adding a temporal dimension to the study of Friedreich's ataxia: the effect of frataxin overexpression in a human cell model |
title_full |
Adding a temporal dimension to the study of Friedreich's ataxia: the effect of frataxin overexpression in a human cell model |
title_fullStr |
Adding a temporal dimension to the study of Friedreich's ataxia: the effect of frataxin overexpression in a human cell model |
title_full_unstemmed |
Adding a temporal dimension to the study of Friedreich's ataxia: the effect of frataxin overexpression in a human cell model |
title_sort |
adding a temporal dimension to the study of friedreich's ataxia: the effect of frataxin overexpression in a human cell model |
publisher |
The Company of Biologists |
series |
Disease Models & Mechanisms |
issn |
1754-8403 1754-8411 |
publishDate |
2018-06-01 |
description |
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. |
topic |
Frataxin Friedreich's ataxia Overexpression Oxidative stress |
url |
http://dmm.biologists.org/content/11/6/dmm032706 |
work_keys_str_mv |
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