Inhibiting SNX14 Alleviates Epileptic Seizures by Regulating GluA2 Degradation via the Lysosomal Pathway

Epilepsy is a common chronic neurological condition, and temporal lobe epilepsy (TLE) is the most common form of refractory epilepsy. However, the underlying causes of TLE remain unclear. Our initial findings revealed that the expression of sorting nexin 14 (SNX14), which is a member of the sorting nexin protein family, was significantly upregulated in brain tissues from both patients with TLE and mouse models of TLE. Moreover, modulation of SNX14 expression in the hippocampus of mice demonstrated that SNX14 downregulation significantly decreased the susceptibility to and severity of seizures, whereas SNX14 overexpression exerted the opposite effects. Mechanistically, we revealed that GluA2, which is a subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor, was a downstream target of SNX14. Further studies indicated that SNX14 modulated GluA2 protein levels by regulating GluA2 degradation via the lysosomal pathway, which in turn influenced glutamatergic synaptic transmission. In conclusion, our findings suggest that the SNX14-GluA2 pathway could be a promising target for the development of novel treatments for epilepsy.