Human Molecular Genetics Advance Access published online on April 17, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp183
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Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPAR
pathway as a therapeutic target in Friedreich's ataxia
1 Program in Neurogenetics, Department of Neurology David Geffen School of Medicine, University of California at Los Angeles, CA 90095 2 Laboratoire de Neurologie Expérimentale, Hôpital Erasme, Université Libre de Bruxelles (ULB), 1070, Belgium 3 Division of Endocrinology, Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium 4 Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), 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 at Daniel Geschwind, MD, PhD, Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Phone: 310-794-6570 Fax: 310-267-2401 Email: dhg{at}ucla.edu
Received February 26, 2009; Revised April 14, 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
) 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 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 pathway affects frataxin levels in vitro, supporting PPAR as a novel therapeutic target in FRDA.
6 These authors co-directed this work.