title: Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1.
abstract: Axonal degeneration is a critical, early event in many acute and chronic neurological disorders. It has been consistently observed after traumatic brain injury, but whether axon degeneration is a driver of traumatic brain injury remains unclear. Molecular pathways underlying the pathology of traumatic brain injury have not been defined, and there is no efficacious treatment for traumatic brain injury. Here we show that mice lacking the mouse Toll receptor adaptor Sarm1 (sterile α/Armadillo/Toll-Interleukin receptor homology domain protein) gene, a key mediator of Wallerian degeneration, demonstrate multiple improved traumatic brain injury-associated phenotypes after injury in a closed-head mild traumatic brain injury model. Sarm1(-/-) mice developed fewer β-amyloid precursor protein aggregates in axons of the corpus callosum after traumatic brain injury as compared to Sarm1(+/+) mice. Furthermore, mice lacking Sarm1 had reduced plasma concentrations of the phophorylated axonal neurofilament subunit H, indicating that axonal integrity is maintained after traumatic brain injury. Strikingly, whereas wild-type mice exibited a number of behavioural deficits after traumatic brain injury, we observed a strong, early preservation of neurological function in Sarm1(-/-) animals. Finally, using in vivo proton magnetic resonance spectroscopy we found tissue signatures consistent with substantially preserved neuronal energy metabolism in Sarm1(-/-) mice compared to controls immediately following traumatic brain injury. Our results indicate that the SARM1-mediated prodegenerative pathway promotes pathogenesis in traumatic brain injury and suggest that anti-SARM1 therapeutics are a viable approach for preserving neurological function after traumatic brain injury.
authors.affiliation: 1 Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA 2 Department of Psychiatry University of Massachusetts Medical School, Worcester, MA 01655, USA nils.henninger@umassmed.edu.
authors.forename: Nils
authors.initials: N
authors.lastname: Henninger
authors.affiliation: 1 Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: James
authors.initials: J
authors.lastname: Bouley
authors.affiliation: 2 Department of Psychiatry University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Elif M
authors.initials: EM
authors.lastname: Sikoglu
authors.affiliation: 3 Divisions of Neurology and Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA.
authors.forename: Jiyan
authors.initials: J
authors.lastname: An
authors.affiliation: 2 Department of Psychiatry University of Massachusetts Medical School, Worcester, MA 01655, USA 4 Department of Radiology University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Constance M
authors.initials: CM
authors.lastname: Moore
authors.affiliation: 1 Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA 2 Department of Psychiatry University of Massachusetts Medical School, Worcester, MA 01655, USA 4 Department of Radiology University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Jean A
authors.initials: JA
authors.lastname: King
authors.affiliation: 3 Divisions of Neurology and Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Bowser
authors.affiliation: 5 Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Freeman
authors.affiliation: 1 Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D051186:Armadillo Domain Proteins / Q000172:deficiency*; D001369:Axons / Q000378:metabolism* / Q000473:pathology*; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology*; D003337:Corpus Callosum / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000172:deficiency*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020127:Recovery of Function / Q000502:physiology*; D014855:Wallerian Degeneration / Q000378:metabolism / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D051186:Armadillo Domain Proteins; D003598:Cytoskeletal Proteins; C543961:SARM1 protein, mouse
keywords: Wallerian degeneration; axon; knockout; traumatic axonal injury; traumatic brain injury