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Title: Neuronal activity controls the antagonistic between PGC-1α and SMRT in regulating antioxidant defences
Author: Soriano Zaragoza, Francesc X. (Francesc Xavier)
Léveillé, F.
Papadia, S.
Bell, K.F.
Puddifoot, C.
Hardingham, G.E.
Keywords: Neurones
Malalties neurodegeneratives
Regulació genètica
Corea de Huntington
Neurodegenerative Diseases
Genetic regulation
Huntington's chorea
Issue Date: 20-Mar-2010
Publisher: Mary Ann Liebert, Inc.
Abstract: Transcriptional coactivators and corepressors often have multiple targets and can have opposing actions on transcription and downstream physiological events. The coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is under-expressed in Huntington's disease and is a regulator of antioxidant defenses and mitochondrial biogenesis. We show that in primary cortical neurons, expression of PGC-1α strongly promotes resistance to excitotoxic and oxidative stress in a cell autonomous manner, whereas knockdown increases sensitivity. In contrast, the transcriptional corepressor silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) specifically antagonizes PGC-1α-mediated antioxidant effects. The antagonistic balance between PGC-1α and SMRT is upset in favor of PGC-1α by synaptic activity. Synaptic activity triggers nuclear export of SMRT reliant on multiple regions of the protein. Concommitantly, synaptic activity post-translationally enhances the transactivating potential of PGC-1α in a p38-dependent manner, as well as upregulating cyclic-AMP response element binding protein-dependent PGC-1α transcription. Activity-dependent targeting of PGC-1α results in enhanced gene expression mediated by the thyroid hormone receptor, a prototypical transcription factor coactivated by PGC-1α and repressed by SMRT. As a consequence of these events, SMRT is unable to antagonize PGC-1α-mediated resistance to oxidative stress in synaptically active neurons. Thus, PGC-1α and SMRT are antagonistic regulators of neuronal vulnerability to oxidative stress. Further, this coactivator<br>corepressor antagonism is regulated by the activity status of the cell, with implications for neuronal viability.
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It is part of: Antioxidants & Redox Signaling, 2010, vol. 14, num. 8, p. 1425-1436
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ISSN: 1523-0864
Appears in Collections:Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)

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