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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, Frédéric Papadia, Sofia Bell, Karen F. S. Puddifoot, Clare Hardingham, Giles E. |
Keywords: | Neurones Malalties neurodegeneratives Regulació genètica Corea de Huntington Neurons 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. |
Note: | Reproducció del document publicat a: http://dx.doi.org/10.1089/ars.2010.3568 |
It is part of: | Antioxidants & Redox Signaling, 2010, vol. 14, num. 8, p. 1425-1436 |
URI: | http://hdl.handle.net/2445/60799 |
Related resource: | http://dx.doi.org/10.1089/ars.2010.3568 |
ISSN: | 1523-0864 |
Appears in Collections: | Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia) |
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