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

Type
Label
  • PGC-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia. (Articolo in rivista) (literal)
Anno
  • 2010-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1371/journal.pone.0010025 (literal)
Alternative label
  • Marmolino D, Manto M, Acquaviva F, Vergara P, Ravella A, MONTICELLI A, Pandolfo M. (2010)
    PGC-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia.
    in PloS one
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Marmolino D, Manto M, Acquaviva F, Vergara P, Ravella A, MONTICELLI A, Pandolfo M. (literal)
Pagina inizio
  • 10025 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 5 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo
  • 3 (literal)
Note
  • ISI Web of Science (WOS) (literal)
  • SCImago (literal)
  • PubMe (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Gruppo Interdipartimentale di Bioinformatica e Biologia Computazionale, Università di Napoli Federico II, Università di Salerno, Naples, Italy Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano, Università degli Studi di Napoli Federico II, Naples, Italy Dipartimento di Scienze Fisiche, Università degli Studi di Napoli Federico II, Naples, Italy Istituto Nazionale di Fisica Nucleare - Sezione di Napoli, Naples, Italy IEOS Istituto di Endocrinologia ed Oncologia Sperimentale, CNR Napoli, Naples, Italy (literal)
Titolo
  • PGC-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia. (literal)
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. (literal)
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