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Scios-Scios at Diamond	SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration Matthew D. Figley , Weixi Gu , Jeffrey D. Nanson , Yun Shi , Yo Sasaki , Katie Cunnea , Alpeshkumar K. Malde , Xinying Jia , Zhenyao Luo , Forhad K. Saikot , Tamim Mosaiab , Veronika Masic , Stephanie Holt , Lauren Hartley-Tassell , Helen Y. Mcguinness , Mohammad K. Manik , Todd Bosanac , Michael J. Landsberg , Philip S. Kerry , Mehdi Mobli , Robert O. Hughes , Jeffrey Milbrandt , Bostjan Kobe , Aaron Diantonio , Thomas Ve Neuron 109, 1118 - 1136.e11 DOI: 10.1016/j.neuron.2021.02.009 Diamond Proposal Number(s): [24981] Show Abstract ▼ Abstract: Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD+)-cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD+, activates SARM1 via an unknown mechanism. Using structural, biochemical, biophysical, and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD+ and show that both metabolites compete for binding to the auto-inhibitory N-terminal armadillo repeat (ARM) domain of SARM1. We report structures of the SARM1 ARM domain bound to NMN and of the homo-octameric SARM1 complex in the absence of ligands. We show that NMN influences the structure of SARM1 and demonstrate via mutagenesis that NMN binding is required for injury-induced SARM1 activation and axon destruction. Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD+ ratio by cleaving residual NAD+, thereby inducing feedforward metabolic catastrophe and axonal demise.	Apr 2021

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Scios-Scios at Diamond

SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration