Neuron:新研究为从根源上治疗神经退行性疾病提供线索  

The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration

作　　者：Kow Essuman  Daniel W. Summers  Yo Sasaki  Xianrong Mao  Aaron DiAntonio  Jeffrey Milbrandt 

机构地区：[1] Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA[2] Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA[3] Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, USA

出　　处：《现代生物医学进展》2017年第17期I0002-I0002,共1页Progress in Modern Biomedicine

摘　　要：对于许多神经退行性疾病来说。比如帕金森病、肌萎缩侧索硬化和外周神经病变，轴突的损失是一个早期的缺陷。当轴突出现损失。神经细胞就无法正常交流，神经系统功能受到损伤。特别是对外周神经病变来说，受损的轴突会触发自毁程序。在一项新研究中。华盛顿大学医学院的科学家们在自毁的轴突中发现一个特殊分子。深入了解损伤如何发生有助于帮助找到阻止其发生的方法。相关研究结果发表在国际学术期刊Neuron上。Axonal degeneration is an early and prominent feature of many neurological disorders. SARM1 is the central executioner of the axonal degeneration pathway that culminates in depletion of axonal NAD⁺, yet the identity of the underlying NAD⁺-depleting enzyme(s) is unknown. Here, in a series of experiments using purified proteins from mammalian cells, bacteria, and a cell-free protein translation system, we show that the SARM1-TIR domain itself has intrinsic NADase activity—cleaving NAD⁺ into ADP-ribose (ADPR), cyclic ADPR, and nicotinamide, with nicotinamide serving as a feedback inhibitor of the enzyme. Using traumatic and vincristine-induced injury models in neurons, we demonstrate that the NADase activity of full-length SARM1 is required in axons to promote axonal NAD⁺ depletion and axonal degeneration after injury. Hence, the SARM1 enzyme represents a novel therapeutic target for axonopathies. Moreover, the widely utilized TIR domain is a protein motif that can possess enzymatic activity.

关 键 词：神经退行性疾病 治疗 国际学术期刊 外周神经 华盛顿大学 帕金森病 神经细胞 神经系统 

分 类 号：Q255[生物学—细胞生物学]