Multifaceted roles of SARM1 in axon degeneration and signaling

Abstract

Axons are considered to be particularly vulnerable components of the nervous system; impairments to a neuron's axon leads to an effective silencing of a neuron's ability to communicate with other cells. Nervous systems have therefore evolved plasticity mechanisms for adapting to axonal damage. These include acute mechanisms that promote the degeneration and clearance of damaged axons and, in some cases, the initiation of new axonal growth and synapse formation to rebuild lost connections. Here we review how these diverse processes are influenced by the therapeutically targetable enzyme SARM1. SARM1 catalyzes the breakdown of NAD+, which, when unmitigated, can lead to rundown of this essential metabolite and axonal degeneration. SARM1's enzymatic activity also triggers the activation of downstream signaling pathways, which manifest numerous functions for SARM1 in development, innate immunity and responses to injury. Here we will consider the multiple intersections between SARM1 and the injury signaling pathways that coordinate cellular adaptations to nervous system damage.

Keywords: MAP Kinase; Nicotinamide Adenine Dinucleotide (NAD); SARM1; TIR domain; axon degeneration; axonal transport; injury signaling.

FIGURE 1

Cell autonomous and non-cell autonomous roles for SARM1 in responses to axonal injury. Each box indicates the cell type SARM1 is acting within, with text color indicating the cell type being impacted by SARM1’s function (same colors indicate cell autonomous, different colors indicate non-autonomous). SARM1’s cell autonomous roles in injured neurons are shown in magenta. In addition to its most well-known for its role in promoting degeneration of the distal stump, SARM1 is also required for additional responses made by injured neurons. These include the JNK- and c-Jun-dependent release of cytokines (Wang et al., 2018), the ability of neurons to regenerate in C. elegans (Julian and Byrne, 2020), and in promoting death of oligodendrocytes in a glaucoma model (Ko et al., 2020). SARM1 also functions within uninjured cells that participate in responses to injury, including uninjured “bystander” neurons (dark blue blue) (Hsu et al., 2021), and immune cells that react to the damage (light blue) (McLaughlin et al., 2019).

FIGURE 2

Intertwining relationships between SARM1 and axonal damage signaling. Multiple pathways converge on SARM1, which itself has several effects. Following axon injury, the Duel-leucine kinase (DLK) initiates a kinase cascade that both promotes SARM1 activation and turnover of the NAD⁺ biosynthetic enzyme NMNAT. Loss of NMNAT further promotes activation of SARM1 via a shift in the ratio of NAD⁺ to its precursor NMN, both of which are allosteric regulators of SARM1. SARM1’s catalytic state is therefore potently tuned by the function of the NMNAT, which is a critical protective factor in axons and neurons (Gilley and Coleman, 2010). This regulation also enables a feed-forward mechanism of SARM1 activation in injured axons and cells that lack NMNAT function, since once SARM1 is activated it can promote its own further activation by lowering NAD⁺ levels. Downstream of SARM1, loss of NAD⁺ leads to axon breakdown via an unclear mechanism, but is thought to be tied to rapid ATP loss and catastrophic metabolic rundown. One of SARM1’s products, cyclic ADP-ribose (cADPR) has increasingly gained prominence in the model of SARM1’s signaling. Acting on multiple calcium channels, cADPR promotes degeneration via Ca²⁺ flux in the axon. There have also been links between this metabolite and SARM1’s protein signaling activities, which act through several MAP kinases to promote axon regeneration (from the axon segment connected to the cell body), cytokine expression, neurite development, and other functions.