dc.contributor |
Universitat de Barcelona |
dc.contributor.author |
Soriano Zaragoza, Francesc X. (Francesc Xavier) |
dc.contributor.author |
Léveillé, Frédéric |
dc.contributor.author |
Papadia, Sofia |
dc.contributor.author |
Bell, Karen F. S. |
dc.contributor.author |
Puddifoot, Clare |
dc.contributor.author |
Hardingham, Giles E. |
dc.date |
2014-12-16T13:50:33Z |
dc.date |
2014-12-16T13:50:33Z |
dc.date |
2010-03-20 |
dc.date |
2014-12-16T13:50:34Z |
dc.identifier.citation |
1523-0864 |
dc.identifier.citation |
604428 |
dc.identifier.uri |
http://hdl.handle.net/2445/60799 |
dc.format |
12 p. |
dc.format |
application/pdf |
dc.language.iso |
eng |
dc.publisher |
Mary Ann Liebert, Inc. |
dc.relation |
Reproducció del document publicat a: http://dx.doi.org/10.1089/ars.2010.3568 |
dc.relation |
Antioxidants & Redox Signaling, 2010, vol. 14, num. 8, p. 1425-1436 |
dc.relation |
http://dx.doi.org/10.1089/ars.2010.3568 |
dc.rights |
(c) Mary Ann Liebert, Inc., 2010 |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.subject |
Neurones |
dc.subject |
Malalties neurodegeneratives |
dc.subject |
Regulació genètica |
dc.subject |
Corea de Huntington |
dc.subject |
Neurons |
dc.subject |
Neurodegenerative diseases |
dc.subject |
Genetic regulation |
dc.subject |
Huntington's chorea |
dc.title |
Neuronal activity controls the antagonistic between PGC-1α and SMRT in regulating antioxidant defences |
dc.type |
info:eu-repo/semantics/article |
dc.type |
info:eu-repo/semantics/publishedVersion |
dc.description.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 corepressor antagonism is regulated by the activity status of the cell, with implications for neuronal viability. |