The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD + Cleavage Activity that Promotes Pathological Axonal Degeneration

Neuron. 2017 Mar 22;93(6):1334-1343.e5. doi: 10.1016/j.neuron.2017.02.022.

Abstract

Axonal degeneration is an early and prominent feature of many neurological disorders. SARM1 is the central executioner of the axonal degeneration pathway that culminates in depletion of axonal NAD+, yet the identity of the underlying NAD+-depleting enzyme(s) is unknown. Here, in a series of experiments using purified proteins from mammalian cells, bacteria, and a cell-free protein translation system, we show that the SARM1-TIR domain itself has intrinsic NADase activity-cleaving NAD+ into ADP-ribose (ADPR), cyclic ADPR, and nicotinamide, with nicotinamide serving as a feedback inhibitor of the enzyme. Using traumatic and vincristine-induced injury models in neurons, we demonstrate that the NADase activity of full-length SARM1 is required in axons to promote axonal NAD+ depletion and axonal degeneration after injury. Hence, the SARM1 enzyme represents a novel therapeutic target for axonopathies. Moreover, the widely utilized TIR domain is a protein motif that can possess enzymatic activity.

Keywords: NAD(+); NADase; SARM1; TIR; Toll/interleukin-1 receptor domain; axonal degeneration; enzyme; innate immunity.

MeSH terms

  • Animals
  • Armadillo Domain Proteins / genetics
  • Armadillo Domain Proteins / metabolism*
  • Axons / metabolism*
  • Axons / pathology
  • Catalytic Domain*
  • Cells, Cultured
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Humans
  • Mice
  • Mice, Knockout
  • NAD / metabolism*
  • NAD+ Nucleosidase / metabolism*
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology

Substances

  • Armadillo Domain Proteins
  • Cytoskeletal Proteins
  • SARM1 protein, mouse
  • NAD
  • NAD+ Nucleosidase