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2010-03-20

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Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/60799

Neuronal activity controls the antagonistic between PGC-1α and SMRT in regulating antioxidant defences

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http://dx.doi.org/10.1089/ars.2010.3568

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.

Subject

Neurones, Malalties neurodegeneratives, Regulació genètica, Corea de Huntington

Subject (English)

Neurons, Neurodegenerative Diseases, Genetic regulation, Huntington's chorea

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Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)

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SORIANO ZARAGOZA, Francesc X. (Francesc Xavier), et al. Neuronal activity controls the antagonistic between PGC-1α and SMRT in regulating antioxidant defences. Antioxidants & Redox Signaling. 2010. Vol. 14, num. 8, pags. 1425-1436. ISSN 1523-0864. [consulted: 19 of August of 2026]. Available at: https://hdl.handle.net/2445/60799

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