Inducible and reversible phenotypes in a novel mouse model of Friedreich’s Ataxia

Friedreich's ataxia (FRDA), the most common inherited ataxia, is caused by recessive mutations that reduce the levels of frataxin (FXN), a mitochondrial iron binding protein. We developed an inducible mouse model of Fxn deficiency that enabled us to control the onset and progression of disease...

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Main Authors:	Vijayendran Chandran, Kun Gao, Vivek Swarup, Revital Versano, Hongmei Dong, Maria C Jordan, Daniel H Geschwind
Format:	Article
Language:	English
Published:	eLife Sciences Publications Ltd 2017-12-01
Series:	eLife
Subjects:	Friedreich's ataxia neurodegeneration frataxin
Online Access:	https://elifesciences.org/articles/30054

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record_format	Article
spelling	doaj-3821ce74dd04473db1e7f21950fd6a462021-05-05T14:01:14ZengeLife Sciences Publications LtdeLife2050-084X2017-12-01610.7554/eLife.30054Inducible and reversible phenotypes in a novel mouse model of Friedreich’s AtaxiaVijayendran Chandran0https://orcid.org/0000-0002-2469-6263Kun Gao1Vivek Swarup2Revital Versano3Hongmei Dong4Maria C Jordan5Daniel H Geschwind6https://orcid.org/0000-0003-2896-3450Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United StatesProgram in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United StatesProgram in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United StatesProgram in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United StatesProgram in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United StatesDepartment of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United StatesProgram in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United StatesFriedreich's ataxia (FRDA), the most common inherited ataxia, is caused by recessive mutations that reduce the levels of frataxin (FXN), a mitochondrial iron binding protein. We developed an inducible mouse model of Fxn deficiency that enabled us to control the onset and progression of disease phenotypes by the modulation of Fxn levels. Systemic knockdown of Fxn in adult mice led to multiple phenotypes paralleling those observed in human patients across multiple organ systems. By reversing knockdown after clinical features appear, we were able to determine to what extent observed phenotypes represent reversible cellular dysfunction. Remarkably, upon restoration of near wild-type FXN levels, we observed significant recovery of function, associated pathology and transcriptomic dysregulation even after substantial motor dysfunction and pathology were observed. This model will be of broad utility in therapeutic development and in refining our understanding of the relative contribution of reversible cellular dysfunction at different stages in disease.https://elifesciences.org/articles/30054Friedreich's ataxianeurodegenerationfrataxin
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Vijayendran Chandran Kun Gao Vivek Swarup Revital Versano Hongmei Dong Maria C Jordan Daniel H Geschwind
spellingShingle	Vijayendran Chandran Kun Gao Vivek Swarup Revital Versano Hongmei Dong Maria C Jordan Daniel H Geschwind Inducible and reversible phenotypes in a novel mouse model of Friedreich’s Ataxia eLife Friedreich's ataxia neurodegeneration frataxin
author_facet	Vijayendran Chandran Kun Gao Vivek Swarup Revital Versano Hongmei Dong Maria C Jordan Daniel H Geschwind
author_sort	Vijayendran Chandran
title	Inducible and reversible phenotypes in a novel mouse model of Friedreich’s Ataxia
title_short	Inducible and reversible phenotypes in a novel mouse model of Friedreich’s Ataxia
title_full	Inducible and reversible phenotypes in a novel mouse model of Friedreich’s Ataxia
title_fullStr	Inducible and reversible phenotypes in a novel mouse model of Friedreich’s Ataxia
title_full_unstemmed	Inducible and reversible phenotypes in a novel mouse model of Friedreich’s Ataxia
title_sort	inducible and reversible phenotypes in a novel mouse model of friedreich’s ataxia
publisher	eLife Sciences Publications Ltd
series	eLife
issn	2050-084X
publishDate	2017-12-01
description	Friedreich's ataxia (FRDA), the most common inherited ataxia, is caused by recessive mutations that reduce the levels of frataxin (FXN), a mitochondrial iron binding protein. We developed an inducible mouse model of Fxn deficiency that enabled us to control the onset and progression of disease phenotypes by the modulation of Fxn levels. Systemic knockdown of Fxn in adult mice led to multiple phenotypes paralleling those observed in human patients across multiple organ systems. By reversing knockdown after clinical features appear, we were able to determine to what extent observed phenotypes represent reversible cellular dysfunction. Remarkably, upon restoration of near wild-type FXN levels, we observed significant recovery of function, associated pathology and transcriptomic dysregulation even after substantial motor dysfunction and pathology were observed. This model will be of broad utility in therapeutic development and in refining our understanding of the relative contribution of reversible cellular dysfunction at different stages in disease.
topic	Friedreich's ataxia neurodegeneration frataxin
url	https://elifesciences.org/articles/30054
work_keys_str_mv	AT vijayendranchandran inducibleandreversiblephenotypesinanovelmousemodeloffriedreichsataxia AT kungao inducibleandreversiblephenotypesinanovelmousemodeloffriedreichsataxia AT vivekswarup inducibleandreversiblephenotypesinanovelmousemodeloffriedreichsataxia AT revitalversano inducibleandreversiblephenotypesinanovelmousemodeloffriedreichsataxia AT hongmeidong inducibleandreversiblephenotypesinanovelmousemodeloffriedreichsataxia AT mariacjordan inducibleandreversiblephenotypesinanovelmousemodeloffriedreichsataxia AT danielhgeschwind inducibleandreversiblephenotypesinanovelmousemodeloffriedreichsataxia
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Inducible and reversible phenotypes in a novel mouse model of Friedreich’s Ataxia

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