Journal article
Enhanced Fyn-tau and NR2B-PSD95 interactions in epileptic foci in experimental models and human epilepsy
Brain communications, Vol.6(5), fcae327
09/02/2024
DOI: 10.1093/braincomms/fcae327
PMCID: PMC11444080
PMID: 39355003
Abstract
Abstract Epilepsy and Alzheimer’s Disease (AD) share some common pathologies such as neurodegeneration, seizures, and impaired cognition. However, the molecular mechanisms of these changes are still largely unknown. Fyn, a Src-family non-receptor tyrosine kinase (SFK), and its interaction with tau in mediating brain pathology in epilepsy and AD can be a potential therapeutic target for disease modification. Although Fyn and tau pathology occurs in both AD and epilepsy, the dynamics of Fyn-tau and PSD95-NR2B interactions affected by seizures and their impact on brain pathology in epilepsy have not been investigated. In this study, we demonstrate a significant increase of Fyn-tau interactions following seizure induction by kainate in both acute and chronic rodent models, and in human epilepsy. In the early phase of epileptogenesis, we show increased Fyn/tau/NR2B/PSD95/neuronal nitric oxide synthase (nNOS) complexes after status epilepticus and a post-synaptic increase of phosphorylated tau (pY18 and AT8), Fyn (pSFK-Y416), and NMDAR (pNR2B-Y1472), and nNOS. Hippocampal Proximity Ligation Assay and co-immunoprecipitation revealed a sustained increase of Fyn-tau and NR2B-PSD95 complexes/binding in rat chronic epilepsy at three months post-status epilepticus. Enhanced Fyn-tau complexes strongly correlated with the frequency of spontaneously recurring convulsive seizures and epileptiform spikes in the chronic epilepsy model. In human epileptic brains, we also identified increased Fyn-tau and NR2B-PSD95 complexes, tau phosphorylation (pY18 and AT8), and Fyn activation (pSFK-Y416), implying the translational and therapeutic potential of these molecular interactions. In tau knockout mice and in rats treated with a Fyn/SFK inhibitor saracatinib, we found a significant reduction of phosphorylated Fyn, tau (AT8 in saracatinib-treated), NR2B, and nNOS, and their interactions (Fyn-tau and NR2B-PSD95 in saracatinib-treated group; NR2B-PSD95 in tau knockout group). The reduction of Fyn-tau and NR2B-PSD95 interactions in the saracatinib-treated group, in contrast to the vehicle-treated group, correlated with the modification in seizure progression in the rat chronic epilepsy model. These findings from animal models and human epilepsy provide evidence for the role of Fyn-tau and NR2B-PSD95 interactions in seizure-induced brain pathology and suggest that blocking such interactions could modify the progression of epilepsy.
Details
- Title: Subtitle
- Enhanced Fyn-tau and NR2B-PSD95 interactions in epileptic foci in experimental models and human epilepsy
- Creators
- Marson Putra - Iowa State UniversityNikhil S Rao - Iowa State UniversityCara Gardner - Iowa State UniversityGuanghao Liu - University of IowaJordan Trommater - Iowa State UniversityMichael Bunney - Iowa State UniversityMeghan Gage - Iowa State UniversityAlexander G Bassuk - University of IowaMarco Hefti - University of IowaGloria Lee - University of IowaThimmasettappa Thippeswamy - Iowa State University
- Resource Type
- Journal article
- Publication Details
- Brain communications, Vol.6(5), fcae327
- DOI
- 10.1093/braincomms/fcae327
- PMID
- 39355003
- PMCID
- PMC11444080
- NLM abbreviation
- Brain Commun
- ISSN
- 2632-1297
- eISSN
- 2632-1297
- Publisher
- OXFORD UNIV PRESS
- Grant note
- National Institutes of Health (NIH): R21NS112779-01A1, R01NS133584-01A1, 5P50HD103556-03, R01AG017753 W. E. Lloyd Endowment Fund: SG2200008
This study was supported by grants from the Office of the Vice President for Research at Iowa State University and the University of Iowa's Office of Research and Economic Development (ORED) (T.T., G.Lee., A.G.B. and M.H.) and the National Institutes of Health (NIH) grants R21NS112779-01A1 (T.T.), R01NS133584-01A1 (T.T.), 5P50HD103556-03 (A.G.B.) and R01AG017753 (G.Le.). This project was also supported by W. E. Lloyd Endowment Fund (SG2200008) to T.T., and AstraZeneca provided saracatinib under the Open Innovation Programme (T.T.).
- Language
- English
- Electronic publication date
- 09/19/2024
- Date published
- 09/02/2024
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Immunology; Neurology (Pediatrics); Internal Medicine
- Record Identifier
- 9984719271202771
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