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.

难治性颞叶癫痫 (TLE) 的一个重要病理特征是神经元丢失。反复发作引起的氧化应激是导致海马神经元丢失的重要机制。烟酰胺腺嘌呤二核苷酸 (NAD) 是一种参与许多生化氧化还原反应的辅酶。烟酰胺单核苷酸腺苷酸转移酶 2 (Nmnat2) 催化 NAD (NADP) 生物合成途径中的一个重要步骤，并被认为是一种神经元维持因子，通过上下文相关机制保护神经元免受损伤。然而，出乎意料的是，Nmnat2 在癫痫中不发挥神经保护作用。我们发现 Nmnat2 在 TLE 小鼠模型中增加。功能获得方法表明，CA1 区 Nmnat2 的过表达增强了癫痫发作的易感性并导致神经元丢失体内。此外，我们发现伴侣功能对于通过 Nmnat2 的功能突变增加细胞凋亡至关重要。最后，体内 Nmnat2 过表达降低了 SOD2 的表达并增加了 FoxO3a。总的来说，我们的研究揭示了 Nmnat2 在癫痫中的新生物学功能，并提供了对癫痫潜在分子事件的新见解。