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

<h4>Background</h4>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 previo...

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Autores principales:	Daniele Marmolino, Mario Manto, Fabio Acquaviva, Paola Vergara, Ajay Ravella, Antonella Monticelli, Massimo Pandolfo
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1ed16c65f7954b3bbaa18b4a705ff543
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spelling	oai:doaj.org-article:1ed16c65f7954b3bbaa18b4a705ff5432021-11-25T06:24:44ZPGC-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia.1932-620310.1371/journal.pone.0010025https://doaj.org/article/1ed16c65f7954b3bbaa18b4a705ff5432010-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20383327/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.Daniele MarmolinoMario MantoFabio AcquavivaPaola VergaraAjay RavellaAntonella MonticelliMassimo PandolfoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 4, p e10025 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Daniele Marmolino Mario Manto Fabio Acquaviva Paola Vergara Ajay Ravella Antonella Monticelli Massimo Pandolfo PGC-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia.
description	<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.
format	article
author	Daniele Marmolino Mario Manto Fabio Acquaviva Paola Vergara Ajay Ravella Antonella Monticelli Massimo Pandolfo
author_facet	Daniele Marmolino Mario Manto Fabio Acquaviva Paola Vergara Ajay Ravella Antonella Monticelli Massimo Pandolfo
author_sort	Daniele Marmolino
title	PGC-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia.
title_short	PGC-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia.
title_full	PGC-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia.
title_fullStr	PGC-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia.
title_full_unstemmed	PGC-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia.
title_sort	pgc-1alpha down-regulation affects the antioxidant response in friedreich's ataxia.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/1ed16c65f7954b3bbaa18b4a705ff543
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PGC-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia.

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