SARM1

Although SARM is known to participate in mitophagy and possibly other yet-unknown cell functions, its primary known function in mammals is mediation of neuronal cell death.[1] Because SARM1 is highly expressed in the nervous system, most studies of SARM1 focus on neuron degeneration, but some SARM1 can be found in many tissues. By cyclizing NAD+ to cADPR, SARM1 functions as a Ca²⁺-signaling enzyme similar to CD38, but SARM1 elevates cADPR much more efficiently than CD38.[2]

SARM1 in response to neuronal injury initiates a cell destruction program (Wallerian degeneration) that catalyze the formation of nicotinamide and adenosine diphosphate ribose (ADPR) or cyclic ADP-ribose (cADPR) from NAD+.[3][2][4] Similarly, SARM1 triggers cell death in the leaves of plants by a Toll-Interleukin receptor (TIR) domain NADase function.[5] Loss of SMAR1 in fruit flies and mice provides protection from axon degeneration.[6]

SARM1 protein plays a central role in the Wallerian degeneration pathway. The gene was first identified in a Drosophila melanogaster mutagenesis screen, and subsequently knockouts of its homologue in mice showed robust protection of transected axons comparable to that of Wld^S mutation (a mouse mutation resulting in slowed Wallerian degeneration).[7][8]

SARM1 activation locally triggers a rapid collapse of NAD⁺ levels in the distal section of the injured axon, which then undergoes degeneration.[9] This collapse in NAD⁺ levels was later shown to be due to SARM1's TIR domain having intrinsic NAD⁺ cleavage activity.[10] The SARM1 protein has four domains, a mitochondrial localization signal, an auto-inhibitory N-terminus region consisting of armadillo/HEAT motifs, two sterile alpha motifs responsible for multimerization, and a C-terminus Toll/Interleukin-1 receptor that possesses enzymatic activity.[10] Activation of SARM1 is sufficient to collapse NAD⁺ levels and initiate the Wallerian degeneration pathway.[9]

The activity of SARM1 helps to explain the protective nature of the survival factors NMNAT1 and NMNAT2, as NMNAT enzymes have been shown to prevent SARM1-mediated depletion of NAD⁺.[4][11] This relationship is further supported by the fact that mice lacking NMNAT2, which are normally not viable, are completely rescued by SARM1 deletion, placing NMNAT2 activity upstream of SARM1.[12] Other pro-degeneration signaling pathways, such as the MAP kinase pathway, have been linked to SARM1 activation. MAPK signaling has been shown to promote the loss of NMNAT2, thereby promoting SARM1 activation, although SARM1 activation also triggers the MAP kinase cascade, indicating some form of feedback loop exists.[13][14]

One explanation for the protective effect of the Wld^S mutation is that the NMNAT1 region, which is normally localized to the soma, substitutes for the labile survival factor NMNAT2 to prevent SARM1 activation when the N-terminal Ube4 region of the WldS protein localizes it to the axon. The axon-protective phenotype of Wld^S mutation is linked to enhanced expression of NMNAT1.[15] The fact that the enhanced survival of Wld^S axons is due to the slower turnover of Wld^S compared to NMNAT2 also helps explain why SARM1 knockout confers longer protection, as SARM1 will be completely inactive regardless of inhibitor activity whereas Wld^S will eventually be degraded. Possibles implications of the SARM1 pathway in regard to human health may be found in animal models which exhibit traumatic brain injury, as mice which contain Sarm1 deletions in addition to Wld^S show decreased axonal damage following injury.[16] Specific mutations in NMNAT2 have linked the Wallerian degeneration mechanism to two neurological diseases.

• SARM1 (Wikigenes collaborative publishing)