PUBLICATION
Enhancing glucose metabolism via gluconeogenesis is therapeutic in a zebrafish model of Dravet syndrome
- Authors
- Banerji, R., Huynh, C., Figueroa, F., Dinday, M.T., Baraban, S.C., Patel, M.
- ID
- ZDB-PUB-210413-13
- Date
- 2021
- Source
- Brain communications 3: fcab004 (Journal)
- Registered Authors
- Baraban, Scott
- Keywords
- epilepsy, gluconeogenesis, metabolism, mitochondria, zebrafish
- MeSH Terms
- none
- PubMed
- 33842883 Full text @ Brain Commun
Citation
Banerji, R., Huynh, C., Figueroa, F., Dinday, M.T., Baraban, S.C., Patel, M. (2021) Enhancing glucose metabolism via gluconeogenesis is therapeutic in a zebrafish model of Dravet syndrome. Brain communications. 3:fcab004.
Abstract
Energy-producing pathways are novel therapeutic targets for the treatment of neurodevelopmental disorders. Here, we focussed on correcting metabolic defects in a catastrophic paediatric epilepsy, Dravet syndrome which is caused by mutations in sodium channel NaV1.1 gene, SCN1A. We utilized a translatable zebrafish model of Dravet syndrome (scn1lab) which exhibits key characteristics of patients with Dravet syndrome and shows metabolic deficits accompanied by down-regulation of gluconeogenesis genes, pck1 and pck2. Using a metabolism-based small library screen, we identified compounds that increased gluconeogenesis via up-regulation of pck1 gene expression in scn1lab larvae. Treatment with PK11195, a pck1 activator and a translocator protein ligand, normalized dys-regulated glucose levels, metabolic deficits, translocator protein expression and significantly decreased electrographic seizures in mutant larvae. Inhibition of pck1 in wild-type larvae mimicked metabolic and behaviour defects observed in scn1lab mutants. Together, this suggests that correcting dys-regulated metabolic pathways can be therapeutic in neurodevelopmental disorders such as Dravet syndrome arising from ion channel dysfunction.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping