Neurotoxin-mediated potent activation of the axon degeneration regulator SARM1.

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cam.depositDate2021-12-17
cam.issuedOnline2021-12-06
cam.orpheus.success2022-03-02: VoR added to Apollo record
dc.contributor.authorLoreto, Andrea
dc.contributor.authorAngeletti, Carlo
dc.contributor.authorGu, Weixi
dc.contributor.authorOsborne, Andrew
dc.contributor.authorNieuwenhuis, Bart
dc.contributor.authorGilley, Jonathan
dc.contributor.authorMerlini, Elisa
dc.contributor.authorArthur-Farraj, Peter
dc.contributor.authorAmici, Adolfo
dc.contributor.authorLuo, Zhenyao
dc.contributor.authorHartley-Tassell, Lauren
dc.contributor.authorVe, Thomas
dc.contributor.authorDesrochers, Laura M
dc.contributor.authorWang, Qi
dc.contributor.authorKobe, Bostjan
dc.contributor.authorOrsomando, Giuseppe
dc.contributor.authorColeman, Michael
dc.contributor.orcidLoreto, Andrea [0000-0001-6535-6436]
dc.contributor.orcidGu, Weixi [0000-0002-1185-3557]
dc.contributor.orcidNieuwenhuis, Bart [0000-0002-2065-2271]
dc.contributor.orcidGilley, Jonathan [0000-0002-9510-7956]
dc.contributor.orcidArthur-Farraj, Peter [0000-0002-1239-9392]
dc.contributor.orcidAmici, Adolfo [0000-0002-1081-7749]
dc.contributor.orcidKobe, Bostjan [0000-0001-9413-9166]
dc.contributor.orcidOrsomando, Giuseppe [0000-0001-6640-097X]
dc.contributor.orcidColeman, Michael [0000-0002-9354-532X]
dc.date.accessioned2021-12-21T00:31:03Z
dc.date.available2021-12-21T00:31:03Z
dc.date.issued2021-12-06
dc.date.updated2021-12-17T17:16:18Z
dc.description.abstractAxon loss underlies symptom onset and progression in many neurodegenerative disorders. Axon degeneration in injury and disease is promoted by activation of the NAD-consuming enzyme SARM1. Here, we report a novel activator of SARM1, a metabolite of the pesticide and neurotoxin vacor. Removal of SARM1 completely rescues mouse neurons from vacor-induced neuron and axon death in vitro and in vivo. We present the crystal structure of the Drosophila SARM1 regulatory domain complexed with this activator, the vacor metabolite VMN, which as the most potent activator yet known is likely to support drug development for human SARM1 and NMNAT2 disorders. This study indicates the mechanism of neurotoxicity and pesticide action by vacor, raises important questions about other pyridines in wider use today, provides important new tools for drug discovery, and demonstrates that removing SARM1 can robustly block programmed axon death induced by toxicity as well as genetic mutation.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.79086
dc.identifier.eissn2050-084X
dc.identifier.issn2050-084X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331634
dc.publishereLife Sciences Publications, Ltd
dc.publisher.departmentDepartment of Clinical Neurosciences
dc.publisher.departmentJohn Van Geest Centre For Brain Repair
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectbiochemistry
dc.subjectchemical biology
dc.subjectmouse
dc.subjectneuroscience
dc.titleNeurotoxin-mediated potent activation of the axon degeneration regulator SARM1.
dc.typeArticle
dcterms.dateAccepted2021-12-05
prism.publicationDate2021
prism.publicationNameElife
prism.volume10
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/S009582/1)
pubs.funder-project-idWellcome Trust (210904/Z/18/Z)
pubs.funder-project-idWellcome Trust (UNS38871)
pubs.funder-project-idNational Eye Research Centre (SAC 041)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
pubs.licence-identifierapollo-deposit-licence-2-1
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.7554/eLife.72823
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