Wang Xiaowan, Zhang Qiao, Bao Ruisi, Zhang Nannan, Wang Yingzhen, Polo-Parada Luis, Tarim Andrew, Alemifar Aidan, Han Xianlin, Wilkins Heather M, Swerdlow Russell H, Wang Xinglong, Ding Shinghua
Department of Bioengineering, University of Missouri, Columbia, MO 65211, USA.
Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA.
Cell Rep. 2017 Aug 29;20(9):2184-2200. doi: 10.1016/j.celrep.2017.08.022.
Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) is the rate-limiting enzyme of the mammalian NAD biosynthesis salvage pathway. Using inducible and conditional knockout (cKO) mice, we show that Nampt gene deletion in adult projection neurons leads to a progressive loss of body weight, hypothermia, motor neuron (MN) degeneration, motor function deficits, paralysis, and death. Nampt deletion causes mitochondrial dysfunction, muscle fiber type conversion, and atrophy, as well as defective synaptic function at neuromuscular junctions (NMJs). When treated with nicotinamide mononucleotide (NMN), Nampt cKO mice exhibit reduced motor function deficits and prolonged lifespan. iNAMPT protein levels are significantly reduced in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, indicating the involvement of NAMPT in ALS pathology. Our findings reveal that neuronal NAMPT plays an essential role in mitochondrial bioenergetics, motor function, and survival. Our study suggests that the NAMPT-mediated NAD biosynthesis pathway is a potential therapeutic target for degenerative MN diseases.
细胞内烟酰胺磷酸核糖转移酶（iNAMPT）是哺乳动物NAD生物合成补救途径的限速酶。利用诱导型和条件性基因敲除（cKO）小鼠，我们发现成年投射神经元中Nampt基因缺失会导致体重逐渐减轻、体温过低、运动神经元（MN）退化、运动功能缺陷、瘫痪和死亡。Nampt缺失会导致线粒体功能障碍、肌纤维类型转换和萎缩，以及神经肌肉接头（NMJ）处的突触功能缺陷。用烟酰胺单核苷酸（NMN）治疗时，Nampt cKO小鼠的运动功能缺陷减少，寿命延长。在肌萎缩侧索硬化症（ALS）患者的脊髓中，iNAMPT蛋白水平显著降低，表明NAMPT参与了ALS病理过程。我们的研究结果表明，神经元NAMPT在线粒体生物能量学、运动功能和生存中起着至关重要的作用。我们的研究表明，NAMPT介导的NAD生物合成途径是退行性MN疾病的潜在治疗靶点。
