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A Warburg-like metabolic program coordinates Wnt, AMPK, and mTOR signaling pathways in epileptogenesis
- Source :
- PLoS ONE, Vol 16, Iss 8, p e0252282 (2021), PLoS ONE
- Publication Year :
- 2021
- Publisher :
- Public Library of Science (PLoS), 2021.
-
Abstract
- Epilepsy is a complex neurological condition characterized by repeated spontaneous seizures and can be induced by initiating seizures known as status epilepticus (SE). Elaborating the critical molecular mechanisms following SE are central to understanding the establishment of chronic seizures. Here, we identify a transient program of molecular and metabolic signaling in the early epileptogenic period, centered on day five following SE in the pre-clinical kainate or pilocarpine models of temporal lobe epilepsy. Our work now elaborates a new molecular mechanism centered around Wnt signaling and a growing network comprised of metabolic reprogramming and mTOR activation. Biochemical, metabolomic, confocal microscopy and mouse genetics experiments all demonstrate coordinated activation of Wnt signaling, predominantly in neurons, and the ensuing induction of an overall aerobic glycolysis (Warburg-like phenomenon) and an altered TCA cycle in early epileptogenesis. A centerpiece of the mechanism is the regulation of pyruvate dehydrogenase (PDH) through its kinase and Wnt target genes PDK4. Intriguingly, PDH is a central gene in certain genetic epilepsies, underscoring the relevance of our elaborated mechanisms. While sharing some features with cancers, the Warburg-like metabolism in early epileptogenesis is uniquely split between neurons and astrocytes to achieve an overall novel metabolic reprogramming. This split Warburg metabolic reprogramming triggers an inhibition of AMPK and subsequent activation of mTOR, which is a signature event of epileptogenesis. Interrogation of the mechanism with the metabolic inhibitor 2-deoxyglucose surprisingly demonstrated that Wnt signaling and the resulting metabolic reprogramming lies upstream of mTOR activation in epileptogenesis. To augment the pre-clinical pilocarpine and kainate models, aspects of the proposed mechanisms were also investigated and correlated in a genetic model of constitutive Wnt signaling (deletion of the transcriptional repressor and Wnt pathway inhibitor HBP1). The results from the HBP1-/- mice provide a genetic evidence that Wnt signaling may set the threshold of acquired seizure susceptibility with a similar molecular framework. Using biochemistry and genetics, this paper outlines a new molecular framework of early epileptogenesis and advances a potential molecular platform for refining therapeutic strategies in attenuating recurrent seizures.
- Subjects :
- Male
Macroglial Cells
Enzyme Metabolism
Kainate receptor
AMP-Activated Protein Kinases
Hippocampus
Biochemistry
Epileptogenesis
Mice
Epilepsy
Status Epilepticus
Cell Signaling
Glucose Metabolism
Animal Cells
Medicine and Health Sciences
Enzyme Chemistry
Wnt Signaling Pathway
WNT Signaling Cascade
Mice, Knockout
Neurons
Multidisciplinary
TOR Serine-Threonine Kinases
Wnt signaling pathway
Brain
Animal Models
Ketones
Signaling Cascades
Chemistry
Experimental Organism Systems
Physical Sciences
Carbohydrate Metabolism
Medicine
Anatomy
Cellular Types
medicine.symptom
Glycolysis
Research Article
Signal Transduction
Pyruvate
Science
Mouse Models
Glial Cells
Status epilepticus
Biology
Research and Analysis Methods
Model Organisms
Genetic model
medicine
Animals
PI3K/AKT/mTOR pathway
Chemical Compounds
Biology and Life Sciences
AMPK
Cell Biology
medicine.disease
Disease Models, Animal
Metabolism
Epilepsy, Temporal Lobe
Astrocytes
Cellular Neuroscience
Enzymology
Animal Studies
Acids
Neuroscience
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- PLOS ONE
- Accession number :
- edsair.doi.dedup.....ee5dfd4b65ef2694abaaa03474f71f5a