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dc.contributor.authorGould, Stacey Anne
dc.contributor.authorGilley, Jonathan
dc.contributor.authorLing, Karen
dc.contributor.authorJafar-Nejad, Paymaan
dc.contributor.authorRigo, Frank
dc.contributor.authorColeman, Michael
dc.date.accessioned2021-12-16T00:30:36Z
dc.date.available2021-12-16T00:30:36Z
dc.date.issued2021
dc.identifier.issn2211-1247
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331536
dc.description.abstractActivation of the pro-degenerative protein SARM1 after diverse physical and disease-relevant injuries causes programmed axon degeneration. Original studies indicate that substantially decreased SARM1 levels are required for neuroprotection. However, we demonstrate, in Sarm1 haploinsufficient mice, that lowering SARM1 levels by 50% delays programmed axon degeneration in vivo after sciatic nerve transection and partially prevents neurite outgrowth defects in mice lacking the pro-survival factor NMNAT2. In vitro, the rate of degeneration in response to traumatic, neurotoxic, and genetic triggers of SARM1 activation is also slowed. Finally, we demonstrate that Sarm1 antisense oligonucleotides decrease SARM1 levels by more than 50% in vitro, which delays or prevents programmed axon degeneration. Combining Sarm1 haploinsufficiency with antisense oligonucleotides further decreases SARM1 levels and prolongs protection after neurotoxic injury. These data demonstrate that axon protection occurs in a Sarm1 gene dose-responsive manner and that SARM1-lowering agents have therapeutic potential, making Sarm1-targeting antisense oligonucleotides a promising therapeutic strategy.
dc.publisherElsevier
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleSarm1 haploinsufficiency or low expression levels after antisense oligonucleotides delay programmed axon degeneration
dc.typeArticle
dc.publisher.departmentDepartment of Psychology
dc.publisher.departmentDepartment of Clinical Neurosciences
dc.date.updated2021-12-14T16:41:22Z
prism.publicationNameCELL REPORTS
dc.identifier.doi10.17863/CAM.78990
dcterms.dateAccepted2021-11-17
rioxxterms.versionofrecord10.1016/j.celrep.2021.110108
rioxxterms.versionVoR
dc.contributor.orcidGould, Stacey [0000-0003-4374-0300]
dc.contributor.orcidColeman, Michael [0000-0002-9354-532X]
dc.identifier.eissn1556-5068
rioxxterms.typeJournal Article/Review
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/K012983/2)
cam.issuedOnline2021-12-14
cam.depositDate2021-12-14
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International