The Contribution of SARM1 to axonal degeneration in CNS inflammatory disorders

BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) that results in demyelination and axonal loss. Efficiently targeting mechanisms of axonal degeneration in MS has the potential to reduce disability but remains an unmet need. Prior research has identified the protein sterile alpha and TIR motif containing 1 (SARM1) as a critical factor that promotes axonal destruction in the program of axonal degeneration known as Wallerian degeneration. SARM1 inactivation reduces axonal degeneration in a variety of contexts including traumatic and toxic injury, but it remains unknown to what extent SARM1 is involved in axonal degeneration triggered by CNS inflammation. METHODS: To test the hypothesis that SARM1 inactivation will reduce the burden of axonal degeneration associated with CNS inflammatory disorders, we first induced mice to have EAE and compared inflammation (CD3) and axonal damage (SMI-31/32, Beta APP) as compared to healthy control mice. We then studied experimental allergic encephalomyelitis (EAE) in Sarm1 knockout (KO) and wild type (WT) mice. We used mice hemizygous for the Thy1-YFP transgene to study axonal damage. Degenerating axons were identified by focal swelling or fragmentation. Beta-APP was also used as a marker of axonal injury. RESULTS: EAE mice had greater inflammation and axonal injury as compared to healthy mice. Sarm1 KO mice are susceptible to developing EAE, with incidence comparable to WT littermates. Analysis of YFP+ axons and Beta-APP showed that Sarm1 KO mice had axonal damage reduced compared to WT littermates. CONCLUSION: Sarm1 is highly expressed in the brain. Preliminary data suggest that SARM1 inactivation may minimize axonal degeneration in CNS inflammatory disorders such as EAE. Further studies are needed to confirm the long-term benefit