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

DOI: 10.1016/j.neuron.2021.02.009

Authors: Matthew D. Figley (University School of Medicine in Saint Louis) , Weixi Gu (University of Queensland) , Jeffrey D. Nanson (University of Queensland) , Yun Shi (Griffith University) , Yo Sasaki (University School of Medicine in Saint Louis) , Katie Cunnea (Evotec (UK) Ltd; Evotec SE) , Alpeshkumar K. Malde (Griffith University) , Xinying Jia (University of Queensland) , Zhenyao Luo (University of Queensland) , Forhad K. Saikot (University of Queensland) , Tamim Mosaiab (Griffith University) , Veronika Masic (Griffith University) , Stephanie Holt (Griffith University) , Lauren Hartley-Tassell (Griffith University) , Helen Y. Mcguinness (University of Queensland) , Mohammad K. Manik (University of Queensland) , Todd Bosanac (Disarm Therapeutics) , Michael J. Landsberg , Philip S. Kerry (Evotec (UK) Ltd; Evotec SE) , Mehdi Mobli (University of Queensland) , Robert O. Hughes (Disarm Therapeutics) , Jeffrey Milbrandt (Washington University School of Medicine in Saint Louis) , Bostjan Kobe (University of Queensland) , Aaron Diantonio (Washington University School of Medicine) , Thomas Ve (Griffith University)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Neuron , VOL 109 , PAGES 1118 - 1136.e11

State: Published (Approved)
Published: April 2021
Diamond Proposal Number(s): 24981

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.

Journal Keywords: NADase; TIR domain; ARM domain; allostery; cryo-EM; X-ray crystallography; nicotinamide riboside

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Scios-Scios at Diamond

Added On: 09/06/2021 11:21

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Neurodegenerative Diseases Neurology Non-Communicable Diseases Structural biology Chemistry Biochemistry

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)