title: Absence of SARM1 rescues development and survival of NMNAT2-deficient axons.
abstract: 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.
authors.affiliation: Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gilley
authors.affiliation: Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, Ancona 60131, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Orsomando
authors.affiliation: Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Nascimento-Ferreira
authors.affiliation: Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK. Electronic address: michael.coleman@babraham.ac.uk.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Coleman
mesh_terms: D000818:Animals; D051186:Armadillo Domain Proteins / Q000378:metabolism*; D001369:Axons / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D051379:Mice; D009410:Nerve Degeneration / Q000473:pathology*; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000172:deficiency / Q000378:metabolism*
chemical_list: D051186:Armadillo Domain Proteins; D003598:Cytoskeletal Proteins; C543961:SARM1 protein, mouse; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C579543:Nmnat2 protein, mouse
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