A significant pathological feature of refractory temporal lobe epilepsy (TLE) is neuronal loss. Oxidative stress caused by repeated seizures is an important mechanism leading to neuronal loss in hippocampus. Nicotinamide-adenine dinucleotide (NAD) a coenzyme that is involved in many biochemical oxidation-reduction reactions. Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) catalyzes an essential step in NAD (NADP) biosynthetic pathwayhas and been considered as a neuronal maintenance factor that protect neurons against insults through context-dependent mechanism. However, it is unexpected that Nmnat2 does not play a neuroprotective role in epilepsy. We found that Nmnat2 was increased in mice model of TLE. Gain-of-function approach revealed that overexpression of Nmnat2 in CA1 area enhanced seizure susceptibility and caused neuronal loss in vivo. Moreover, we found that the chaperone function was essential to increased apoptosis through the function mutation of Nmnat2. Finally, Nmnat2 overexpression in vivo reduced in expression of SOD2 and increased FoxO3a. Overall, our study discloses a new biological function of Nmnat2 in epilepsy and provides novel insights into the molecular events underlying epilepsy.
Keywords: Neuronal death; Nmnat2; Oxidative stress; Seizure susceptibility; Temporal lobe epilepsy.
Copyright © 2020 Elsevier Inc. All rights reserved.