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Human Molecular Genetics Advance Access originally published online on April 17, 2009
Human Molecular Genetics 2009 18(13):2452-2461; doi:10.1093/hmg/ddp183
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© 2009 The Author(s)
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.

Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPAR{gamma} pathway as a therapeutic target in Friedreich’s ataxia

Giovanni Coppola1, Daniele Marmolino2, Daning Lu1, Qing Wang1, Miriam Cnop3,4, Myriam Rai2, Fabio Acquaviva5, Sergio Cocozza5, Massimo Pandolfo2,{dagger} and Daniel H. Geschwind1,*,{dagger}

1 Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA 2 Laboratoire de Neurologie Expérimentale 3 Division of Endocrinology 4 Laboratory of Experimental Medicine, Hôpital Erasme, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium 5 Department of Cellular and Molecular Biology, University of Naples ‘Federico II’, IEOS CNR, Via Pansini 5, 80131 Naples, Italy

* To whom correspondence should be addressed. Tel: +1 3107946570; Fax: +1 3102672401; Email: dhg{at}ucla.edu

Received February 26, 2009; Accepted April 14, 2009

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 (PPAR{gamma}) 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 PPAR{gamma} 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 PPAR{gamma} pathway affects frataxin levels in vitro, supporting PPAR{gamma} as a novel therapeutic target in FRDA.

{dagger} These authors co-directed this work.


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