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

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 N...

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Published in:Neuron (Cambridge, Mass.) Mass.), 2021-04, Vol.109 (7), p.1118-1136.e11
Main Authors: Figley, Matthew D., Gu, Weixi, Nanson, Jeffrey D., Shi, Yun, Sasaki, Yo, Cunnea, Katie, Malde, Alpeshkumar K., Jia, Xinying, Luo, Zhenyao, Saikot, Forhad K., Mosaiab, Tamim, Masic, Veronika, Holt, Stephanie, Hartley-Tassell, Lauren, McGuinness, Helen Y., Manik, Mohammad K., Bosanac, Todd, Landsberg, Michael J., Kerry, Philip S., Mobli, Mehdi, Hughes, Robert O., Milbrandt, Jeffrey, Kobe, Bostjan, DiAntonio, Aaron, Ve, Thomas
Format: Article
Language:English
Subjects:
Adenine
allostery
Animals
ARM domain
Armadillo Domain Proteins - genetics
Armadillo Domain Proteins - metabolism
Axons - pathology
cryo-EM
Cytokines
Cytoskeletal Proteins - genetics
Cytoskeletal Proteins - metabolism
Enzyme Activation
Enzymes
HEK293 Cells
Humans
Hypotheses
Interleukin 1
Kinases
Metabolism
Mice
Mice, Knockout
Models, Molecular
Molecular Dynamics Simulation
Mutagenesis
NAD
NAD - metabolism
NADase
Nerve Degeneration - genetics
Nerve Degeneration - pathology
Neurodegeneration
Neurodegenerative diseases
Nicotinamide Mononucleotide - metabolism
nicotinamide riboside
Nicotinamide-Nucleotide Adenylyltransferase - genetics
Protein Conformation
TIR domain
X-ray crystallography
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Summary: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. •SARM1 is activated by an increase in the ratio of NMN to NAD+•NMN and NAD+ compete for binding to the auto-inhibitory ARM domain of SARM1•NMN binding influences the structure of SARM1•NMN binding is required for injury-induced SARM1 activation and axon destruction Figley et al. demonstrate that SARM1, an inducible pro-degenerative NADase, is a metabolic sensor activated by an increase in the NMN/NAD+ ratio. The authors provide structural and functional insights into SARM1 regulation, which expands our understanding of SARM1 as a druggable target, with implications for a wide range of neurodegenerative diseases.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2021.02.009