Loss of Sarm1 Mitigates Axonal and Neuronal Degeneration and Promotes Neuronal Repair After Ischemic Stroke

Axonal degeneration is a core feature of ischemic brain injury that limits functional recovery (1). The pro-degenerative molecule Sarm1 is required for Wallerian axon degeneration after traumatic and chemotoxic nerve injuries (2), however it is unclear if a similar mechanism mediates axonal degradation after ischemic injury. Here we show that loss of Sarm1 results in profound attenuation of axonal degeneration after focal ischemia to the subcortical white matter. Moreover, absence of Sarm1 significantly promotes the survival of neurons remote from but connected to the infarct after ischemic injuries to the subcortical white matter as well as to the cortex. To further understand the mechanism of Sarm1-/- mediated neuronal protection, we performed differential gene expression analyses of wildtype and Sarm1-/- stroke-injured neurons and found that the loss of Sarm1 activates a pro-growth molecular program that promotes new axon and synapse formation after white matter ischemia. Using a functional genomics approach to recapitulate such a molecular program in Sarm1-/- neurons, we identify molecular compounds sufficient to enhance cortical neurite outgrowth in vitro, and all of which elicit a conserved epigenetic signature promoting axonogenesis. These results indicate that Sarm1 promotes axonal degeneration and concurrently inhibits an axonal reparative program encoded at the level of the epigenome that can be modulated pharmacologically. Our findings thus reveal a novel role for Sarm1 as a crucial regulator of both axonal degeneration and axonal remodeling after ischemic stroke. SIGNIFICANCE STATEMENTAxon degeneration is a pivotal event following ischemic stroke, however the mechanism of white matter loss in stroke is unknown. We demonstrate that the pro-degenerative molecule Sarm1 is required for axonal and neuronal degeneration after ischemic injuries, and that loss of Sarm1 surprisingly induces the activation of a reparative program driving new axon and synapse formation. Using functional genomics, we uncover molecular candidates that phenocopy this pro-growth molecular signature in Sarm1-/- neurons, and show that these compounds are sufficient to promote de novo axonal growth via an epigenetic mechanism. Our results thus reveal a novel role for Sarm1 as a regulator of both axonal degeneration and axonal remodeling after ischemia, and identify pharmacologic candidates to promote axonal repair in stroke.