title: Neuronal activity controls the antagonistic balance between peroxisome proliferator-activated receptor-γ coactivator-1α and silencing mediator of retinoic acid and thyroid hormone receptors in regulating antioxidant defenses.
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. Concomitantly, 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.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Soriano
authors.forename: Frédéric
authors.initials: F
authors.lastname: Léveillé
authors.forename: Sofia
authors.initials: S
authors.lastname: Papadia
authors.forename: Karen F S
authors.initials: KF
authors.lastname: Bell
authors.forename: Clare
authors.initials: C
authors.lastname: Puddifoot
authors.forename: Giles E
authors.initials: GE
authors.lastname: Hardingham
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D056985:Nuclear Receptor Co-Repressor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D056985:Nuclear Receptor Co-Repressor 2; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C569757:silencing mediator of retinoic acid and thyroid hormone receptors, rat; D048051:p38 Mitogen-Activated Protein Kinases