We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia.
- Authors
Coppola, Giovanni; Marmolino, Daniele; Lu, Daning; Wang, Qing; Cnop, Miriam; Rai, Myriam; Acquaviva, Fabio; Cocozza, Sergio; Pandolfo, Massimo; Geschwind, Daniel H.
- Abstract
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.
- Publication
Human Molecular Genetics, 2009, Vol 18, Issue 13, p2452
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddp183