Sterile alpha (SAM) and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1) is an autoinhibitory NAD-consuming enzyme that is activated by the accumulation of nicotinamide mononucleotide (NMN) during axonal injury. Its activation mechanism is not fully understood. 1
Axon degeneration contributes to the disruption of neuronal circuit function in diseased and injured nervous systems. Severed axons degenerate following the activation of an evolutionarily conserved signaling pathway, which culminates in the activation of SARM1 in mammals to execute the pathological depletion of the metabolite NAD+. SARM1 NADase activity is activated by the NAD+ precursor nicotinamide mononucleotide (NMN). In mammals, keeping NMN levels low potently preserves axons after injury. 2
Here we explored pharmacological strategies that modulate NMN and NAD+ metabolism, namely the inhibition of the NMN-synthesizing enzyme NAMPT, activation of the nicotinic acid riboside (NaR) salvage pathway and inhibition of the NMNAT2-degrading DLK MAPK pathway in an axotomy model in vitro. 3
SARM1 is an inducible TIR-domain NAD+ hydrolase that mediates pathological axon degeneration. SARM1 is activated by an increased ratio of NMN to NAD+, which competes for binding to an allosteric activating site. When NMN binds, the TIR domain is released from autoinhibition, activating its NAD+ hydrolase activity. 4
SARM1 is an inducible NAD+ hydrolase that is the central executioner of pathological axon loss. Recently, we elucidated the molecular mechanism of SARM1 activation, demonstrating that SARM1 is a metabolic sensor regulated by the levels of NAD+ and its precursor, nicotinamide mononucleotide (NMN), via their competitive binding to an allosteric site within the SARM1 N-terminal ARM domain. In healthy neurons with abundant NAD+, binding of NAD+ blocks access of NMN to this allosteric site. However, with injury or disease the levels of the NAD+ biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD+ ratio and thereby promoting NMN binding to the SARM1 allosteric site, which in turn induces a conformational change activating the SARM1 NAD+ hydrolase. 5
Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD+ ratio by cleaving residual NAD+, thereby inducing feedforward metabolic catastrophe and axonal demise. 6
>>These findings highlight that the pro-degenerative activity of NMN is context-dependent (healthy neuron vs sick neuron). When NMN levels increase in an intact axon containing NMNAT2, NMN activates SARM1 NADase activity, but it is also converted to NAD+, countering SARM1 activation and promoting axon survival.<<
>> By contrast, the loss of the short-lived NMNAT2 protein after axon injury eliminates this compensatory effect and the resulting increase in NMN levels without concomitant increases in NAD+ causes SARM1 activation and triggers axon degeneration. 6<<
1. Hou, Y. N. et al. A conformation-specific nanobody targeting the nicotinamide mononucleotide-activated state of SARM1. Nat. Commun. 13, 7898 (2022).
2. Llobet Rosell, A. et al. The NAD+ precursor NMN activates dSarm to trigger axon degeneration in Drosophila. eLife 11, e80245 (2022).
3. Alexandris, A. S. et al. Protective effects of NAMPT or MAPK inhibitors and NaR on Wallerian degeneration of mammalian axons. Neurobiol. Dis. 171, 105808 (2022).
4. Wu, T. et al. Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss. Cell Rep. 37, 109872 (2021).
5. Sasaki, Y. et al. Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection. Exp. Neurol. 345, 113842 (2021).
6. Figley, M. D. et al. SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. Neuron 109, 1118-1136.e11 (2021).
