RT Journal Article
SR Electronic
T1 Potent activation of SARM1 by NMN analogue VMN underlies vacor neurotoxicity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.18.304261
DO 10.1101/2020.09.18.304261
A1 Andrea Loreto
A1 Carlo Angeletti
A1 Weixi Gu
A1 Andrew Osborne
A1 Bart Nieuwenhuis
A1 Jonathan Gilley
A1 Peter Arthur-Farraj
A1 Elisa Merlini
A1 Adolfo Amici
A1 Zhenyao Luo
A1 Lauren Hartley-Tassell
A1 Thomas Ve
A1 Laura M. Desrochers
A1 Qi Wang
A1 Bostjan Kobe
A1 Giuseppe Orsomando
A1 Michael P. Coleman
YR 2021
UL http://biorxiv.org/content/early/2021/06/23/2020.09.18.304261.abstract
AB Axon loss underlies symptom onset and progression in many neurodegenerative disorders. Axon degeneration in injury and disease is promoted by activation of the nicotinamide adenine dinucleotide (NAD)-consuming enzyme SARM1 (sterile alpha and TIR motif-containing protein 1). Here, we report vacor mononucleotide (VMN), a metabolite of the pesticide and neurotoxin vacor, as the most potent yet SARM1 activator. Removal of SARM1 shows complete rescue from vacor-induced neuron and axon death in vitro and in vivo. We present the crystal structure of VMN bound to the Drosophila SARM1 regulatory armadillo-repeat domain, thus facilitating drug development to prevent SARM1 activation in human disease. This study indicates the likely mechanism of action of vacor as a pesticide and lethal neurotoxin in humans, provides important new tools for drug discovery, and further demonstrates that SARM1 removal can permanently block programmed axon death specifically induced by toxicity as well as genetic mutation.Competing Interest StatementThis work is in part funded by a BBSRC/AstraZeneca Industrial Partnership Award and Q.W. and L.M.D. were employees of AstraZeneca for part of the project. B.K., T.V., Z.L. and W.G. receive research funding from Disarm Therapeutics, a wholly-owned subsidiary of Eli Lilly & Co., Cambridge, MA, USA, but they had no role in the research presented here.