Stepwise activation of SARM1 for cell death and axon degeneration revealed by a biosynthetic NMN mimic

• DOI: 10.1073/pnas.2424906122
• Publication Date: 2025-02-18T16:40:41Z
• Authors: Yinpin Huang; Jun Zhang; Wenbin Zhang; Jie Chen; Sijia Chen; Qincui Wu; Sanduo Zheng; Xiaodong Wang

Axon degeneration, driven by the NAD + hydrolyzing enzyme SARM1, is an early pathological hallmark of numerous neurodegenerative diseases. SARM1 exists in inactive form and activated following nerve injury. However, precise molecular mechanism underlying activation remains to be fully elucidated. In this study, we report identification a potent proactivator G10, which converted into direct activator (M1) nicotinamide phosphoribosyltransferase. Cryoelectron microscopy structures bound M1, as well M1 nonhydrolyzable analog (1AD), captured two intermediate states active state, revealing stepwise activation. Further, introducing disulfide bond prevent conformational transitions between mediated stabilized its blocked M1-induced cell death. Together, these findings propose sequential, model for offer framework developing potential inhibitors treatment