The identification of the mechanism of action of vacor, an environmental neurotoxin which causes neurodegeneration by activating the pro-degenerative enzyme SARM1, raises important questions on SARM1 as a mediator of environmental neurotoxicity and has implications for drug discovery.

Cryo-EM shows that the NADase activity of SARM1 is allosterically inhibited by physiological concentrations of NAD+ that stabilizes an auto-inhibited conformation of SARM1, explaining how NAD+ depletion may inflict neurodegeneration.

The first-in-class cell-permeant fluorescent probe provides direct and visual evidence of SARM1 activation in axonal degeneration and identified the first covalent, allosteric inhibitor of SARM1 acting on the NAD-binding pocket in the ARM domain.

A phase transition of TIR-1/SARM1 induced by either pathogen or non-pathogen stress potentiates its intrinsic NADase activity, which activates the p38 PMK-1 signaling cascade to induce protective immune defenses in Caenorhabditis elegans intestinal epithelial cells.

TIR-1 regulates both repair and destruction on either side of an injury axon.

BisMapR reveals strand-specific R-loops with high resolution at small-scale genomic features including bidirectionally transcribed promoters and enhancers.

A mouse model of retinal degeneration reveals a common mechanism for axonal degeneration and photoreceptor cell death and identifies SARM1 as a therapeutic candidate for retinopathies.

Axonal metabolic flux analysis demonstrates that expression of NMNAT1 blocks axonal degeneration in cultured mouse neurons not by altering NAD+ synthesis, but rather by inhibiting injury-induced, SARM1-dependent NAD+ consumption.

Axon degeneration due to loss of mitochondria is suppressed by CaMKII activity and MAP kinase signaling.

A chemical probe was characterized for potency, selectivity, and ability to alter CARM1-dependent epigenetic plasticity against cancer cell invasion.