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Exp Neurol. 2012 Oct;237(2):396-406. doi: 10.1016/j.expneurol.2012.06.031. Epub 2012 Jul 6.

Ablation of PGC1 beta prevents mTOR dependent endoplasmic reticulum stress response.

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1
University of Cambridge Metabolic Research Laboratories, NIHR Cambridge Biomedical Research Centre Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. ajv22@cam.ac.uk

Erratum in

  • Exp Neurol. 2013 Jan;239:101.

Abstract

Mitochondria dysfunction contributes to the pathophysiology of obesity, diabetes, neurodegeneration and ageing. The peroxisome proliferator-activated receptor-gamma coactivator-1β (PGC-1β) coordinates mitochondrial biogenesis and function as well as fatty acid metabolism. It has been suggested that endoplasmic reticulum (ER) stress may be one of the mechanisms linking mitochondrial dysfunction and these pathologies. Here we investigate whether PGC-1β ablation affects the ER stress response induced by specific nutritional and pharmacological challenges in the CNS. By using flow cytometry, western blot, real time PCR and several pharmacological and nutritional interventions in PGC-1β knock out and WT mice, we confirmed that PGC-1β coordinates mitochondria function in brain and reported for the first time that a) ablation of PGC-1β is associated with constitutive activation of mTORC1 pathway associated with increased basal GRP78 protein levels in hypothalamus and cortex of animals fed chow diet; and b) in animals fed chronically with high fat diet (HFD) or high protein diet (HPD), we observed a failure to appropriately induce ER stress response in the absence of PGC-1β, associated with an increase in mTOR pathway phosphorylation. This contrasted with the appropriate upregulation of ER stress response observed in wild type littermates. Additionally, inefficient in vitro induction of ER stress by thapsigargin seems result in apoptotic neuronal cell death in PGC-1β KO. Our data indicate that PGC-1β is required for a neuronal ER response to nutritional stress imposed by HFD and HPD diets and that genetic ablation of PGC-1β might increase the susceptibility to neuronal damage and cell death.

PMID:
22771762
PMCID:
PMC3549498
DOI:
10.1016/j.expneurol.2012.06.031
[Indexed for MEDLINE]
Free PMC Article
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