title: SARM1 activation triggers axon degeneration locally via NAD⁺ destruction.
abstract: Axon degeneration is an intrinsic self-destruction program that underlies axon loss during injury and disease. Sterile alpha and TIR motif-containing 1 (SARM1) protein is an essential mediator of axon degeneration. We report that SARM1 initiates a local destruction program involving rapid breakdown of nicotinamide adenine dinucleotide (NAD(+)) after injury. We used an engineered protease-sensitized SARM1 to demonstrate that SARM1 activity is required after axon injury to induce axon degeneration. Dimerization of the Toll-interleukin receptor (TIR) domain of SARM1 alone was sufficient to induce locally mediated axon degeneration. Formation of the SARM1 TIR dimer triggered rapid breakdown of NAD(+), whereas SARM1-induced axon destruction could be counteracted by increased NAD(+) synthesis. SARM1-induced depletion of NAD(+) may explain the potent axon protection in Wallerian degeneration slow (Wld(s)) mutant mice.
authors.affiliation: Department of Genetics, Washington University Medical School, Saint Louis, MO, USA.
authors.forename: Josiah
authors.initials: J
authors.lastname: Gerdts
authors.affiliation: Department of Developmental Biology, Washington University Medical School, Saint Louis, MO, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Brace
authors.affiliation: Department of Genetics, Washington University Medical School, Saint Louis, MO, USA.
authors.forename: Yo
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Department of Developmental Biology, Washington University Medical School, Saint Louis, MO, USA. Hope Center for Neurological Disorders, Saint Louis, MO, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: DiAntonio
authors.affiliation: Department of Genetics, Washington University Medical School, Saint Louis, MO, USA. Hope Center for Neurological Disorders, Saint Louis, MO, USA. jmilbrandt@wustl.edu.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
mesh_terms: D000818:Animals; D051186:Armadillo Domain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009243:NAD / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D059348:Peripheral Nerve Injuries / Q000378:metabolism*; D055503:Protein Multimerization; D014855:Wallerian Degeneration / Q000378:metabolism* / Q000473:pathology
chemical_list: D051186:Armadillo Domain Proteins; D003598:Cytoskeletal Proteins; C543961:SARM1 protein, mouse; D009243:NAD