Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1
Department of Neurology; Department of Psychiatry; Department of Neurobiology; Freeman Lab
Molecular and Cellular Neuroscience | Nervous System Diseases | Neurology
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 adaptorSarm1(sterile alpha/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 beta-amyloid precursor protein aggregates in axons of the corpus callosum after traumatic brain injury as compared toSarm1(+/+)mice. Furthermore, mice lackingSarm1had 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 inSarm1(-/-)animals. Finally, usingin vivoproton magnetic resonance spectroscopy we found tissue signatures consistent with substantially preserved neuronal energy metabolism inSarm1(-/-)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.
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Citation: Brain. 2016 Apr;139(Pt 4):1094-105. doi: 10.1093/brain/aww001. Epub 2016 Feb 11. Link to article on publisher's site
Wallerian degeneration, axon, knockout, traumatic axonal injury, traumatic brain injury
Henninger, Nils; Bouley, James P.; Sikoglu, Elif M.; An, Jiyan; Moore, Constance M.; King, Jean A.; Bowser, Robert; Freeman, Marc R.; and Brown, Robert H. Jr., "Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1" (2016). Neurology Publications and Presentations. 425.