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Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia
Friedreich’s ataxia (FRDA), the most common inherited ataxia, is characterized by focal neurodegeneration, diabetes mellitus and life-threatening cardiomyopathy. Frataxin, which is significantly reduced in patients with this recessive disorder, is a mitochondrial iron-binding protein, but how its de...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Oxford University Press
2009
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694693/ https://www.ncbi.nlm.nih.gov/pubmed/19376812 http://dx.doi.org/10.1093/hmg/ddp183 |
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author | Coppola, Giovanni Marmolino, Daniele Lu, Daning Wang, Qing Cnop, Miriam Rai, Myriam Acquaviva, Fabio Cocozza, Sergio Pandolfo, Massimo Geschwind, Daniel H. |
author_facet | Coppola, Giovanni Marmolino, Daniele Lu, Daning Wang, Qing Cnop, Miriam Rai, Myriam Acquaviva, Fabio Cocozza, Sergio Pandolfo, Massimo Geschwind, Daniel H. |
author_sort | Coppola, Giovanni |
collection | PubMed |
description | Friedreich’s ataxia (FRDA), the most common inherited ataxia, is characterized by focal neurodegeneration, diabetes mellitus and life-threatening cardiomyopathy. Frataxin, which is significantly reduced in patients with this recessive disorder, is a mitochondrial iron-binding protein, but how its deficiency leads to neurodegeneration and metabolic derangements is not known. We performed microarray analysis of heart and skeletal muscle in a mouse model of frataxin deficiency, and found molecular evidence of increased lipogenesis in skeletal muscle, and alteration of fiber-type composition in heart, consistent with insulin resistance and cardiomyopathy, respectively. Since the peroxisome proliferator-activated receptor gamma (PPARγ) pathway is known to regulate both processes, we hypothesized that dysregulation of this pathway could play a key role in frataxin deficiency. We confirmed this by showing a coordinate dysregulation of the PPARγ coactivator Pgc1a and transcription factor Srebp1 in cellular and animal models of frataxin deficiency, and in cells from FRDA patients, who have marked insulin resistance. Finally, we show that genetic modulation of the PPARγ pathway affects frataxin levels in vitro, supporting PPARγ as a novel therapeutic target in FRDA. |
format | Text |
id | pubmed-2694693 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-26946932009-06-10 Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia Coppola, Giovanni Marmolino, Daniele Lu, Daning Wang, Qing Cnop, Miriam Rai, Myriam Acquaviva, Fabio Cocozza, Sergio Pandolfo, Massimo Geschwind, Daniel H. Hum Mol Genet Articles Friedreich’s ataxia (FRDA), the most common inherited ataxia, is characterized by focal neurodegeneration, diabetes mellitus and life-threatening cardiomyopathy. Frataxin, which is significantly reduced in patients with this recessive disorder, is a mitochondrial iron-binding protein, but how its deficiency leads to neurodegeneration and metabolic derangements is not known. We performed microarray analysis of heart and skeletal muscle in a mouse model of frataxin deficiency, and found molecular evidence of increased lipogenesis in skeletal muscle, and alteration of fiber-type composition in heart, consistent with insulin resistance and cardiomyopathy, respectively. Since the peroxisome proliferator-activated receptor gamma (PPARγ) pathway is known to regulate both processes, we hypothesized that dysregulation of this pathway could play a key role in frataxin deficiency. We confirmed this by showing a coordinate dysregulation of the PPARγ coactivator Pgc1a and transcription factor Srebp1 in cellular and animal models of frataxin deficiency, and in cells from FRDA patients, who have marked insulin resistance. Finally, we show that genetic modulation of the PPARγ pathway affects frataxin levels in vitro, supporting PPARγ as a novel therapeutic target in FRDA. Oxford University Press 2009-07-01 2009-04-17 /pmc/articles/PMC2694693/ /pubmed/19376812 http://dx.doi.org/10.1093/hmg/ddp183 Text en © 2009 The Author(s) http://creativecommons.org/licenses/by-nc/2.0/uk/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Coppola, Giovanni Marmolino, Daniele Lu, Daning Wang, Qing Cnop, Miriam Rai, Myriam Acquaviva, Fabio Cocozza, Sergio Pandolfo, Massimo Geschwind, Daniel H. Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia |
title | Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia |
title_full | Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia |
title_fullStr | Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia |
title_full_unstemmed | Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia |
title_short | Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia |
title_sort | functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the pparγ pathway as a therapeutic target in friedreich’s ataxia |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694693/ https://www.ncbi.nlm.nih.gov/pubmed/19376812 http://dx.doi.org/10.1093/hmg/ddp183 |
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