SARM1: an unexpected evolutionary journey: from neuronal protection to axonal degeneration

Wallerian axonal degeneration (WD) does not manifest in the nematode C. elegans as in other model animals (e.g., drosophila, zebrafish, mouse), and may be viewed as a neurodegenerative process that had emerged and progressed during evolution. The complete reliance of WD on the NADase activity of SARM1, a protein that is also expressed in C. elegans (designated TIR-1), suggests that certain evolutionary modifications had turned this protein from a preserver of axon integrity under stress in C. elegans into an executioner of damaged axons in higher organisms.

The domain composition of SARM1 includes an N terminal ARM, two SAM and one TIR domains that mediate auto-inhibition, oligomerization, and NADase activity, respectively. Mechanistically, following nerve injury, the NADase activity of SARM1 is induced and consumes the entire stores of the metabolite NAD+, bringing about axonal death.

Here, to find out the molecular basis for the functional discrepancy between the C. elegans and human orthologs, we perform structural, biochemical, and functional investigations that explain their underlying functional discrepancy.