PGC-1alpha Down-Regulation Affects the Antioxidant Response in Friedreich's Ataxia

PLoS ONE 5(4): e10025. doi:10.1371/journal.pone.0010025
Daniele Marmolino1, Mario Manto1,2, Fabio Acquaviva3, Paola Vergara3, Ajay Ravella1, Antonella Monticelli4, Massimo Pandolfo1*

1 Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles (ULB), Brussels, Belgium, 2 Fonds National de la Recherche Scientifique (FNRS), Brussels, Belgium, 3 Department of Cellular and Molecular Biology, University of Naples “Federico II”, Naples, Italy, 4 IEOS, Consiglio Nazionale delle Ricerche (CNR), Naples, Italy

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Background

Cells from individuals with Friedreich's ataxia (FRDA) show reduced activities of antioxidant enzymes and cannot up-regulate their expression when exposed to oxidative stress. This blunted antioxidant response may play a central role in the pathogenesis. We previously reported that Peroxisome Proliferator Activated Receptor Gamma (PPARγ) Coactivator 1-alpha (PGC-1α), a transcriptional master regulator of mitochondrial biogenesis and antioxidant responses, is down-regulated in most cell types from FRDA patients and animal models.
Methodology/Principal Findings

We used primary fibroblasts from FRDA patients and the knock in-knock out animal model for the disease (KIKO mouse) to determine basal superoxide dismutase 2 (SOD2) levels and the response to oxidative stress induced by the addition of hydrogen peroxide. We measured the same parameters after pharmacological stimulation of PGC-1α. Compared to control cells, PGC-1α and SOD2 levels were decreased in FRDA cells and did not change after addition of hydrogen peroxide. PGC-1α direct silencing with siRNA in control fibroblasts led to a similar loss of SOD2 response to oxidative stress as observed in FRDA fibroblasts. PGC-1α activation with the PPARγ agonist (Pioglitazone) or with a cAMP-dependent protein kinase (AMPK) agonist (AICAR) restored normal SOD2 induction. Treatment of the KIKO mice with Pioglitazone significantly up-regulates SOD2 in cerebellum and spinal cord.
Conclusions/Significance

PGC-1α down-regulation is likely to contribute to the blunted antioxidant response observed in cells from FRDA patients. This response can be restored by AMPK and PPARγ agonists, suggesting a potential therapeutic approach for FRDA.

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