Gerdts Josiah, Brace E J, Sasaki Yo, DiAntonio Aaron, Milbrandt Jeffrey
Department of Genetics, Washington University Medical School, Saint Louis, MO, USA.
Department of Developmental Biology, Washington University Medical School, Saint Louis, MO, USA.
Science. 2015 Apr 24;348(6233):453-7. doi: 10.1126/science.1258366. Epub 2015 Apr 23.
Axon degeneration is an intrinsic self-destruction program that underlies axon loss during injury and disease. Sterile alpha and TIR motif-containing 1 (SARM1) protein is an essential mediator of axon degeneration. We report that SARM1 initiates a local destruction program involving rapid breakdown of nicotinamide adenine dinucleotide (NAD(+)) after injury. We used an engineered protease-sensitized SARM1 to demonstrate that SARM1 activity is required after axon injury to induce axon degeneration. Dimerization of the Toll-interleukin receptor (TIR) domain of SARM1 alone was sufficient to induce locally mediated axon degeneration. Formation of the SARM1 TIR dimer triggered rapid breakdown of NAD(+), whereas SARM1-induced axon destruction could be counteracted by increased NAD(+) synthesis. SARM1-induced depletion of NAD(+) may explain the potent axon protection in Wallerian degeneration slow (Wld(s)) mutant mice.
轴突退化是一种内在的自我破坏程序，是损伤和疾病期间轴突损失的基础。含无菌α和TIR基序的1（SARM1）蛋白是轴突退化的关键介质。我们报告称，SARM1在损伤后启动了一个局部破坏程序，涉及烟酰胺腺嘌呤二核苷酸（NAD(+)）的快速分解。我们使用一种工程化的蛋白酶敏感型SARM1来证明，轴突损伤后需要SARM1活性来诱导轴突退化。单独的SARM1的Toll-白细胞介素受体（TIR）结构域二聚化足以诱导局部介导的轴突退化。SARM1 TIR二聚体的形成引发了NAD(+)的快速分解，而增加NAD(+)合成可以抵消SARM1诱导的轴突破坏。SARM1诱导的NAD(+)消耗可能解释了慢 Wallerian 变性（Wld(s)）突变小鼠中强大的轴突保护作用。
