Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is an evolutionarily conserved nicotinamide adenine dinucleotide (NAD+) synthase located in the cytoplasm and Golgi apparatus. It has a crucial role in synthesizing NAD+, which is an essential cofactor for energy metabolism. The NMNAT2-NAD+-SARM1 axis is closely related to Wallerian degeneration and is involved in various biological processes like axonal transport regulation. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions [1].

Mouse and cultured neuron models have shown that NMNAT2 in glutamatergic neurons is required for axonal survival. Loss of NMNAT2 from cortical glutamatergic neurons impacts axonal transport, energetic metabolism, and morphological integrity. Exogenous NAD+ supplementation or inhibiting SARM1 can prevent axonal deficits caused by NMNAT2 loss [4,5]. In 6-OHDA-lesioned rat models of Parkinson's disease, dysbiosis of gut microbiota suppresses NMNAT2 expression, exacerbating neurobehavioral deficits and oxidative stress response, which can be rescued by fecal microbiota transplantation (FMT) or NMNAT2 restoration [3].

In conclusion, NMNAT2 is essential for maintaining axonal health by ensuring efficient vesicular glycolysis required for fast axonal transport through NAD+ homeostasis. Its study using KO/CKO mouse models has revealed its significance in neurodegenerative diseases, including Parkinson's disease, and other conditions like chemotherapy-induced peripheral neuropathy, where it may serve as a potential therapeutic target [1,2,3,4,5].