Products Cited in Publications Worldwide Target inhibition of NAT10-mediated ac4C modification prevents seizure behavior in mice

Target inhibition of NAT10-mediated ac4C modification prevents seizure behavior in mice

Zhang, Aomei; Yang, Jingwen; Wang, Meng; Li, Yujia; Hu, Tao; Xie, Jialin; Xu, Yang; Cao, Wenyu

DOI: PMID:

Abstract

N4-acetylation of (ac4C), catalyzed by its only known enzyme N-acetyltransferase 10 (NAT10), facilitates cellular mRNA translation and stability, but its function in brain disorders especially epilepsy is poorly understood. By using pentylenetetrazole (PTZ) induced mouse model of epilepsy, we first displayed spatiotemporally expression of ac4C and NAT10 in the mouse brain. To corroborate the alteration of ac4C and NAT10 in epilepsy, we used acute PTZ, chronic PTZ and intrahippocampal kainic acid (IHKA) mouse model. We then utilized a combination of viral tool and pharmacological approaches to implicate NAT10 mediated ac4C modification in seizure behaviors. We found that the expression of ac4C was increased in epileptic brain tissues in mouse models of epilepsy, which might be due to the up-regulated NAT10. Block of NAT10 led to both reduced brain ac4C level and resistance to PTZ or KA-induced seizure behavior, while hippocampal over-expression of NAT10 causes exacerbated seizure behavior. In support of such a role, our data demonstrated that the loss or gains of ac4C modification could normalize or exacerbate neuronal over-activation in epileptic brain tissues, respectively. Mechanically, we observed that block the NAT10 or over-expression NAT10 lead to reduced or enhanced BDNF, respectively. While the BDNF pathway inhibitor rescued the hippocampal NAT10 over-expression induced aggravated seizure behavior in the chronic PTZ treated mice. Therefore, our work provides the first demonstration of the ac4C levels in an epilepsy mice model, targeted to prevent ac4C by NAT10 inhibition seems to be effective in preventing and treating epilepsy.

Keywords

ac4C ; NAT10 ; Seizure ; Hippocampus ; IEGs

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