Genetic ablation of Sarm1 attenuates expression and mislocalization of phosphorylated TDP-43 after mouse repetitive traumatic brain injury.

Axon Behavior Brain injury Glial scar Haploinsufficiency Interleukin Neurodegeneration SARM1 TDP-43 Tau

Journal

Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673

Informations de publication

Date de publication:
20 Dec 2023
Historique:
received: 15 08 2023
accepted: 06 12 2023
medline: 21 12 2023
pubmed: 21 12 2023
entrez: 21 12 2023
Statut: epublish

Résumé

Traumatic 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.

Identifiants

pubmed: 38124145
doi: 10.1186/s40478-023-01709-4
pii: 10.1186/s40478-023-01709-4
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

206

Subventions

Organisme : NINDS NIH HHS
ID : K08 NS091499
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS131756
Pays : United States

Informations de copyright

© 2023. The Author(s).

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Auteurs

Elif O Dogan (EO)

Department of Neurology, University of Massachusetts Chan Medical School, 55 Lake Ave, North, Worcester, MA, 01655, USA.

James Bouley (J)

Department of Neurology, University of Massachusetts Chan Medical School, 55 Lake Ave, North, Worcester, MA, 01655, USA.

Jianjun Zhong (J)

Department of Neurology, University of Massachusetts Chan Medical School, 55 Lake Ave, North, Worcester, MA, 01655, USA.
Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Ashley L Harkins (AL)

Department of Neurology, University of Massachusetts Chan Medical School, 55 Lake Ave, North, Worcester, MA, 01655, USA.
Graduate Program in Neuroscience, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA.
Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Allison M Keeler (AM)

Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Department of Pediatrics, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Daryl A Bosco (DA)

Department of Neurology, University of Massachusetts Chan Medical School, 55 Lake Ave, North, Worcester, MA, 01655, USA.

Robert H Brown (RH)

Department of Neurology, University of Massachusetts Chan Medical School, 55 Lake Ave, North, Worcester, MA, 01655, USA.

Nils Henninger (N)

Department of Neurology, University of Massachusetts Chan Medical School, 55 Lake Ave, North, Worcester, MA, 01655, USA. Nils.Henninger@umassmed.edu.
Department of Psychiatry, University of Massachusetts Chan Medical School, 55 Lake Ave, North, Worcester, MA, 01655, USA. Nils.Henninger@umassmed.edu.

Classifications MeSH