SARM1 signaling mechanisms in the injured nervous system

Abstract

Axon degeneration is a prominent feature of the injured nervous system, occurs across neurological diseases, and drives functional loss in neural circuits. We have seen a paradigm shift in the last decade with the realization that injured axons are capable of actively driving their own destruction through the sterile-alpha and TIR motif containing 1 (SARM1) protein. Early studies of Wallerian degeneration highlighted a central role for NAD⁺ metabolites in axon survival, and this association has grown even stronger in recent years with a deeper understanding of SARM1 biology. Here, we review our current knowledge of SARM1 function in vivo and our evolving understanding of its complex architecture and regulation by injury-dependent changes in the local metabolic environment. The field is converging on a model whereby SARM1 acts as a sensor for metabolic changes that occur after injury and then drives catastrophic NAD⁺ loss to promote degeneration. However, a number of observations suggest that SARM1 biology is more complicated, and there remains much to learn about how SARM1 governs nervous system responses to injury or disease.

Figure 1.

Components of the TIR-1 MAPK signaling cascade in worms, flies and mammals

Figure 2.. Nmnat2/NAD⁺ depletion model for axon degeneration

Nmnat2 is a survival factor transported down axons from the cell body that generates NAD⁺ from NMN. After axotomy, the labile Nmnat2 molecule is depleted from distal severed axons, NAD⁺ drops, NMN rises, and Sarm1 is activated. In mammalian neurons MAPK signaling (based on MKK4/7 phosphorylation) in axons peaks early, NAD⁺ drops hours later, and axon fragmentation begins. Time reflects events in DRG primary cultures, in vivo times are much longer. (see text for details)

Figure 3.. SARM1 signals in two distinct phases

Within 2 hours after axotomy the TIR-1-like MAPK cascade is activated in both injured axons and uninjured adjacent bystander neurons. Phase I leads to a broad suppression of neurophysiology in both severed and intact bystander neurons, with injury signals being spread to bystander neurons through glial Draper/MEGF10 signaling. Phase I does not require Axundead or dSarm NAD⁺ hydrolase function. During Phase II, bystanders recover functionally and severed axons activate dSarm/SARM1-mediated axon degeneration through dSarm NAD⁺ hydrolase activity and Axundead.

Figure 4.. Model for SARM1 activation

SARM1 exists in an autoinhibited conformation where the ARM domains lock the TIR domains in an inactive conformation (top left). Hiding the ARM domains (top right) reveals that the TIR domains are connected to the SAM2 domains via a flexible (and unresolved) linker. A transient high concentration of NMN triggers a conformation change, releasing the ARM domains and likely causing the TIR domains to dimerize (possibly on top of the SAM2 domains), resulting in the formation of catalytically active TIRs (bottom). Note, this is a hypothetical model, and although active TIR domains are displayed as dimers, other oligomerization states are possible.