PGC-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia.

Daniele Marmolino,Fabio Acquaviva,Massimo Pandolfo,Ajay Ravella,Antonella Monticelli,Mario Manto,Paola Vergara,Antoni L Andreu

doi:10.1371/journal.pone.0010025

Abstract

BackgroundCells 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 FindingsWe 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/SignificancePGC-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.

Highlights

Friedreich’s ataxia (FRDA) is an autosomal recessive inherited disorder affecting approximately 1 in every 40 000 individuals [1] in Western Europe
PGC-1a reduction is associated to reduced superoxide dismutase 2 (SOD2) in FRDA fibroblasts and does not increase after H2O2 incubation
The baseline expression levels of SOD2 and PGC-1a were reduced in fibroblasts from FRDA patients when compared to healthy controls cells (Fig. 1A)

Summary

Introduction

Friedreich’s ataxia (FRDA) is an autosomal recessive inherited disorder affecting approximately 1 in every 40 000 individuals [1] in Western Europe. Patients are homozygous for this mutation, or, rarely, are compound heterozygotes for the GAA repeat expansion and a different FXN loss-of-function mutation. They show severely reduced levels of the FXN-encoded mitochondrial protein frataxin, a highly conserved protein with homologs in all eukaryotes and in Gram-negative bacteria [8]. 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 (PPARc) Coactivator 1-alpha (PGC-1a), a transcriptional master regulator of mitochondrial biogenesis and antioxidant responses, is down-regulated in most cell types from FRDA patients and animal models

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Results

Conclusion