2. Academic Validation
  3. SARM1 activation triggers axon degeneration locally via NAD⁺ destruction

SARM1 activation triggers axon degeneration locally via NAD⁺ destruction

  • Science. 2015 Apr 24;348(6233):453-7. doi: 10.1126/science.1258366.
Josiah Gerdts 1,  E J Brace 2,  Yo Sasaki 1,  Aaron DiAntonio 3,  Jeffrey Milbrandt 4
Affiliations

Affiliations

  • 1 Department of Genetics, Washington University Medical School, Saint Louis, MO, USA.
  • 2 Department of Developmental Biology, Washington University Medical School, Saint Louis, MO, USA.
  • 3 Department of Developmental Biology, Washington University Medical School, Saint Louis, MO, USA. Hope Center for Neurological Disorders, Saint Louis, MO, USA.
  • 4 Department of Genetics, Washington University Medical School, Saint Louis, MO, USA. Hope Center for Neurological Disorders, Saint Louis, MO, USA. [email protected].
PMID: 25908823 DOI: 10.1126/science.1258366
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.

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