Absence of SARM1 Rescues Development and Survival of NMNAT2-Deficient Axons

Summary

SARM1 function and nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) loss both promote axon degeneration, but their relative relationship in the process is unknown. Here, we show that NMNAT2 loss and resultant changes to NMNAT metabolites occur in injured SARM1-deficient axons despite their delayed degeneration and that axon degeneration specifically induced by NMNAT2 depletion requires SARM1. Strikingly, SARM1 deficiency also corrects axon outgrowth in mice lacking NMNAT2, independently of NMNAT metabolites, preventing perinatal lethality. Furthermore, NAMPT inhibition partially restores outgrowth of NMNAT2-deficient axons, suggesting that the NMNAT substrate, NMN, contributes to this phenotype. NMNAT2-depletion-dependent degeneration of established axons and restricted extension of developing axons are thus both SARM1 dependent, and SARM1 acts either downstream of NMNAT2 loss and NMN accumulation in a linear pathway or in a parallel branch of a convergent pathway. Understanding the pathway will help establish relationships with other modulators of axon survival and facilitate the development of effective therapies for axonopathies.

Graphical Abstract

Highlights

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  SARM1 is required for WLD ^S-sensitive axon degeneration caused by NMNAT2 depletion

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  SARM1 deficiency rescues developmental axon defects caused by a lack of NMNAT2

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  Mice lacking NMNAT2 and SARM1 are viable

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  Lowering NMN by inhibiting NAMPT partially rescues growth of NMNAT2-deficient axons

Abstract

Gilley et al. find that SARM1 promotes axon degeneration after NMNAT2 depletion and limits outgrowth of axons constitutively lacking NMNAT2. The NMNAT substrate NMN also appears to be pro-degenerative in both situations. Restricted outgrowth of NMNAT2-deficient axons is thus mechanistically related to the degeneration of established axons.