Proteomic signature of the Dravet syndrome in the genetic Scn1a-A1783V mouse model

Autor: Valentina Di Liberto, Ali Rezaei, Heidrun Potschka, Nina Miljanovic, R. Maarten van Dijk, Stefanie M. Hauck
Přispěvatelé: Miljanovic, Nina, Hauck, Stefanie M., van Dijk, R. Maarten, Di Liberto, Valentina, Rezaei, Ali, Potschka, Heidrun
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Male
Proteomics
0301 basic medicine
Proteome
Hippocampus
Epilepsies
Myoclonic
Haploinsufficiency
Scn1a
Synaptic Transmission
Elevated Plus Maze Test
Epilepsy
Mice
0302 clinical medicine
Tandem Mass Spectrometry
11-beta-Hydroxysteroid Dehydrogenase Type 1
Genetic epilepsy
Carbon-Nitrogen Ligases
Gene Knock-In Techniques
Gliosis
Neuronal Plasticity
Behavior
Animal
Epileptic encephalopathy
Immunohistochemistry
Astrogliosis
Neurology
Disease Progression
Female
Signal Transduction
RC321-571
Dopamine and cAMP-Regulated Phosphoprotein 32
Neovascularization
Physiologic
Neurosciences. Biological psychiatry. Neuropsychiatry
Biology
Nitric Oxide
03 medical and health sciences
Dravet syndrome
medicine
Animals
Hyperthermia
Social Behavior
ras-GRF1
Proteomic Profiling
medicine.disease
Vascular Endothelial Growth Factor Receptor-2
NAV1.1 Voltage-Gated Sodium Channel
Disease Models
Animal
030104 developmental biology
Rotarod Performance Test
Synaptic plasticity
Epileptic Encephalopathy
Genetic Epilepsy
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Open Field Test
Neuroscience
030217 neurology & neurosurgery
Chromatography
Liquid
Zdroj: Neurobiol. Dis. 157:105423 (2021)
Neurobiology of Disease, Vol 157, Iss, Pp 105423-(2021)
Popis: Background Dravet syndrome is a rare, severe pediatric epileptic encephalopathy associated with intellectual and motor disabilities. Proteomic profiling in a mouse model of Dravet syndrome can provide information about the molecular consequences of the genetic deficiency and about pathophysiological mechanisms developing during the disease course. Methods A knock-in mouse model of Dravet syndrome with Scn1a haploinsufficiency was used for whole proteome, seizure, and behavioral analysis. Hippocampal tissue was dissected from two- (prior to epilepsy manifestation) and four- (following epilepsy manifestation) week-old male mice and analyzed using LC-MS/MS with label-free quantification. Proteomic data sets were subjected to bioinformatic analysis including pathway enrichment analysis. The differential expression of selected proteins was confirmed by immunohistochemical staining. Results The findings confirmed an increased susceptibility to hyperthermia-associated seizures, the development of spontaneous seizures, and behavioral alterations in the novel Scn1a-A1873V mouse model of Dravet syndrome. As expected, proteomic analysis demonstrated more pronounced alterations following epilepsy manifestation. In particular, proteins involved in neurotransmitter dynamics, receptor and ion channel function, synaptic plasticity, astrogliosis, neoangiogenesis, and nitric oxide signaling showed a pronounced regulation in Dravet mice. Pathway enrichment analysis identified several significantly regulated pathways at the later time point, with pathways linked to synaptic transmission and glutamatergic signaling dominating the list. Conclusion In conclusion, the whole proteome analysis in a mouse model of Dravet syndrome demonstrated complex molecular alterations in the hippocampus. Some of these alterations may have an impact on excitability or may serve a compensatory function, which, however, needs to be further confirmed by future investigations. The proteomic data indicate that, due to the molecular consequences of the genetic deficiency, the pathophysiological mechanisms may become more complex during the course of the disease. As a result, the management of Dravet syndrome may need to consider further molecular and cellular alterations. Ensuing functional follow-up studies, this data set may provide valuable guidance for the future development of novel therapeutic approaches.
Databáze: OpenAIRE
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