1. SARM1 is a metabolic sensor activated by an increased NMN/NAD + ratio to trigger axon degeneration.
- Author
-
Figley MD, Gu W, Nanson JD, Shi Y, Sasaki Y, Cunnea K, Malde AK, Jia X, Luo Z, Saikot FK, Mosaiab T, Masic V, Holt S, Hartley-Tassell L, McGuinness HY, Manik MK, Bosanac T, Landsberg MJ, Kerry PS, Mobli M, Hughes RO, Milbrandt J, Kobe B, DiAntonio A, and Ve T
- Subjects
- Animals, Enzyme Activation, HEK293 Cells, Humans, Mice, Mice, Knockout, Models, Molecular, Molecular Dynamics Simulation, Mutagenesis, Nicotinamide-Nucleotide Adenylyltransferase genetics, Protein Conformation, Armadillo Domain Proteins genetics, Armadillo Domain Proteins metabolism, Axons pathology, Cytoskeletal Proteins genetics, Cytoskeletal Proteins metabolism, NAD metabolism, Nerve Degeneration genetics, Nerve Degeneration pathology, Nicotinamide Mononucleotide metabolism
- 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., Competing Interests: Declaration of interests A.D. and J.M. are co-founders, scientific advisory board members, and shareholders of Disarm Therapeutics. B.K. is shareholder of Disarm Therapeutics. Y. Sasaki and B.K. are consultants to Disarm Therapeutics. B.K. and T.V. receive research funding from Disarm Therapeutics. R.O.H. and T.B. are employees and shareholders in Disarm Therapeutics. K.C. and P.S.K. are employees of Evotec (UK) Ltd. The authors declare no additional competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF