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

Abstract

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 (PPARgamma) Coactivator 1-alpha (PGC-1alpha), 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-1alpha. Compared to control cells, PGC-1alpha and SOD2 levels were decreased in FRDA cells and did not change after addition of hydrogen peroxide. PGC-1alpha direct silencing with siRNA in control fibroblasts led to a similar loss of SOD2 response to oxidative stress as observed in FRDA fibroblasts. PGC-1alpha activation with the PPARgamma 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-1alpha 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 PPARgamma agonists, suggesting a potential therapeutic approach for FRDA.

• Authors: Daniele Marmolino, Mario Manto, Fabio Acquaviva, Paola Vergara, Ajay Ravella, Antonella Monticelli, Massimo Pandolfo
• Journal: PloS one (PLoS One) Vol. 5 Issue 4 Pg. e10025 (Apr 07 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 20383327 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Heat-Shock Proteins
• PPAR gamma
• PPARGC1A protein, human
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Transcription Factors
• Hydrogen Peroxide
• Superoxide Dismutase
• superoxide dismutase 2
• Cyclic AMP-Dependent Protein Kinases

Topics

• Animals
• Antioxidants (metabolism)
• Case-Control Studies
• Cells, Cultured
• Cyclic AMP-Dependent Protein Kinases
• Down-Regulation (genetics)
• Friedreich Ataxia (metabolism, pathology)
• Heat-Shock Proteins (genetics)
• Humans
• Hydrogen Peroxide (pharmacology)
• Mice
• Mice, Knockout
• Oxidative Stress
• PPAR gamma
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Superoxide Dismutase (analysis)
• Transcription Factors (genetics)