Treatment of Epilepsy Using a Targeted p38γ Kinase Gene Therapy

Authors

Nicolle Morey
Magdalena Przybyla
Julia van der Hoven
Yazi D Ke
Fabien Delerue
Janet van Eersel
Lars M Ittner

Publication Date

12-2-2022

Journal

Science Advances

Abstract

Hyperphosphorylated microtubule-associated protein tau has been implicated in dementia, epilepsy, and other neurological disorders. In contrast, site-specific phosphorylation of tau at threonine 205 (T205) by the kinase p38γ was shown to disengage tau from toxic pathways, serving a neuroprotective function in Alzheimer's disease. Using a viral-mediated gene delivery approach in different mouse models of epilepsy, we show that p38γ activity-enhancing treatment reduces seizure susceptibility, restores neuronal firing patterns, reduces behavioral deficits, and ameliorates epilepsy-induced deaths. Furthermore, we show that p38γ-mediated phosphorylation of tau at T205 is essential for this protection in epilepsy, as a lack of this critical interaction reinstates pathological features and accelerates epilepsy in vivo. Hence, our work provides a scope to harness p38γ as a future therapy applicable to acute neurological conditions.

Keywords

Animals, Mice, Epilepsy, Seizures, Phosphorylation, Alzheimer Disease, Disease Models, Animal

Comments

Supplementary Material

PMID: 36459557

DOI

10.1126/sciadv.add2577

PMID

36459557

PMCID

PMC10936047

PubMedCentral® Posted Date

December 2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes