Treatment of epilepsy using a targeted p38y kinase gene therapy

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 p38y 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 p38y activity- enhancing treatment reduces seizure susceptibility, restores neuronal firing patterns, reduces behavioral deficits, and ameliorates epilepsy-induced deaths. Furthermore, we show that p38y-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 p38y as a future therapy applicable to acute neurological conditions.

Automated summary

Hyperphosphorylated tau protein is involved in various neurological disorders, while site-specific phosphorylation of tau at T205 by p38y kinase can protect against Alzheimer's disease. Delivery of p38y through gene transfer reduces seizure susceptibility, restores normal neuronal activity, improves behavioral deficits, and prevents epilepsy-induced deaths. Additionally, p38y-mediated phosphorylation of tau at T205 plays a crucial role in protecting against epilepsy.