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


RESULTS
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
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.
Marmolino
Daniele
D
Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles, Brussels, Belgium.
Manto
Mario
M
Acquaviva
Fabio
F
Vergara
Paola
P
Ravella
Ajay
A
Monticelli
Antonella
A
Pandolfo
Massimo
M
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases; D015536:Down-Regulation / Q000235:genetics*; D005621:Friedreich Ataxia / Q000378:metabolism / Q000473:pathology*; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013482:Superoxide Dismutase / Q000032:analysis; D014157:Transcription Factors / Q000235:genetics*; D000099156:Superoxide Dismutase 2
D000975:Antioxidants; D017868:Cyclic AMP-Dependent Protein Kinases; D006360:Heat-Shock Proteins; D006861:Hydrogen Peroxide; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013482:Superoxide Dismutase; D014157:Transcription Factors; D000099156:Superoxide Dismutase 2; C486497:PPARGC1A protein, human
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