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dc.contributor.authorDogan, Elif O
dc.contributor.authorBouley, James
dc.contributor.authorZhong, Jianjun
dc.contributor.authorHarkins, Ashley L
dc.contributor.authorKeeler, Allison M
dc.contributor.authorBosco, Daryl A
dc.contributor.authorBrown, Robert H
dc.contributor.authorHenninger, Nils
dc.date.accessioned2024-02-07T14:09:04Z
dc.date.available2024-02-07T14:09:04Z
dc.date.issued2023-12-20
dc.identifier.citationDogan EO, Bouley J, Zhong J, Harkins AL, Keeler AM, Bosco DA, Brown RH Jr, Henninger N. Genetic ablation of Sarm1 attenuates expression and mislocalization of phosphorylated TDP-43 after mouse repetitive traumatic brain injury. Acta Neuropathol Commun. 2023 Dec 20;11(1):206. doi: 10.1186/s40478-023-01709-4. PMID: 38124145; PMCID: PMC10731794.en_US
dc.identifier.eissn2051-5960
dc.identifier.doi10.1186/s40478-023-01709-4en_US
dc.identifier.pmid38124145
dc.identifier.urihttp://hdl.handle.net/20.500.14038/53034
dc.description.abstractTraumatic brain injury (TBI), particularly when moderate-to-severe and repetitive, is a strong environmental risk factor for several progressive neurodegenerative disorders. Mislocalization and deposition of transactive response DNA binding protein 43 (TDP-43) has been reported in both TBI and TBI-associated neurodegenerative diseases. It has been hypothesized that axonal pathology, an early event after TBI, may promote TDP-43 dysregulation and serve as a trigger for neurodegenerative processes. We sought to determine whether blocking the prodegenerative Sarm1 (sterile alpha and TIR motif containing 1) axon death pathway attenuates TDP-43 pathology after TBI. We subjected 111 male Sarm1 wild type, hemizygous, and knockout mice to moderate-to-severe repetitive TBI (rTBI) using a previously established injury paradigm. We conducted serial neurological assessments followed by histological analyses (NeuN, MBP, Iba-1, GFAP, pTDP-43, and AT8) at 1 month after rTBI. Genetic ablation of the Sarm1 gene attenuated the expression and mislocalization of phosphorylated TDP-43 (pTDP-43) and accumulation of pTau. In addition, Sarm1 knockout mice had significantly improved cortical neuronal and axonal integrity, functional deficits, and improved overall survival after rTBI. In contrast, removal of one Sarm1 allele delayed, but did not prevent, neurological deficits and neuroaxonal loss. Nevertheless, Sarm1 haploinsufficient mice showed significantly less microgliosis, pTDP-43 pathology, and pTau accumulation when compared to wild type mice. These data indicate that the Sarm1-mediated prodegenerative pathway contributes to pathogenesis in rTBI including the pathological accumulation of pTDP-43. This suggests that anti-Sarm1 therapeutics are a viable approach for preserving neurological function after moderate-to-severe rTBI.en_US
dc.language.isoenen_US
dc.relation.ispartofActa Neuropathologica Communicationsen_US
dc.relation.urlhttps://doi.org/10.1186/s40478-023-01709-4en_US
dc.rights© The Author(s) 2023. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.en_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectAxonen_US
dc.subjectBehavioren_US
dc.subjectBrain injuryen_US
dc.subjectGlial scaren_US
dc.subjectHaploinsufficiencyen_US
dc.subjectInterleukinen_US
dc.subjectNeurodegenerationen_US
dc.subjectSARM1en_US
dc.subjectTDP-43en_US
dc.subjectTauen_US
dc.titleGenetic ablation of Sarm1 attenuates expression and mislocalization of phosphorylated TDP-43 after mouse repetitive traumatic brain injuryen_US
dc.typeJournal Articleen_US
dc.source.journaltitleActa neuropathologica communications
dc.source.volume11
dc.source.issue1
dc.source.beginpage206
dc.source.endpage
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryEngland
dc.identifier.journalActa neuropathologica communications
refterms.dateFOA2024-02-07T14:09:06Z
dc.contributor.departmentHorae Gene Therapy Centeren_US
dc.contributor.departmentMorningside Graduate School of Biomedical Sciencesen_US
dc.contributor.departmentNeurologyen_US
dc.contributor.departmentNeuroNexus Instituteen_US
dc.contributor.departmentPediatricsen_US
dc.contributor.departmentPsychiatryen_US
dc.contributor.studentAshley L Harkins
dc.description.thesisprogramNeuroscience


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© The Author(s) 2023. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use,
sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and
the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this
article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included
in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The
Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available
in this article, unless otherwise stated in a credit line to the data.
Except where otherwise noted, this item's license is described as © The Author(s) 2023. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.