Emergence of SARM1 as a Potential Therapeutic Target for Wallerian-type Diseases

Cell Chem Biol. 2020 Jan 16;27(1):1-13. doi: 10.1016/j.chembiol.2019.11.002. Epub 2019 Nov 21.


Wallerian degeneration is a neuronal death pathway that is triggered in response to injury or disease. Death was thought to occur passively until the discovery of a mouse strain, i.e., Wallerian degeneration slow (WLDS), which was resistant to degeneration. Given that the WLDS mouse encodes a gain-of-function fusion protein, its relevance to human disease was limited. The later discovery that SARM1 (sterile alpha and toll/interleukin receptor [TIR] motif-containing protein 1) promotes Wallerian degeneration suggested the existence of a pathway that might be targeted therapeutically. More recently, SARM1 was found to execute degeneration by hydrolyzing NAD+. Notably, SARM1 knockdown or knockout prevents neuron degeneration in response to a range of insults that lead to peripheral neuropathy, traumatic brain injury, and neurodegenerative disease. Here, we discuss the role of SARM1 in Wallerian degeneration and the opportunities to target this enzyme therapeutically.

Keywords: NAD(+); SARM1; neurodegeneration; therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Armadillo Domain Proteins / antagonists & inhibitors*
  • Armadillo Domain Proteins / chemistry
  • Armadillo Domain Proteins / metabolism
  • Cytoskeletal Proteins / antagonists & inhibitors*
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / metabolism
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Neurodegenerative Diseases / drug therapy*
  • Neurodegenerative Diseases / metabolism
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Wallerian Degeneration / drug therapy*
  • Wallerian Degeneration / metabolism


  • Armadillo Domain Proteins
  • Cytoskeletal Proteins
  • Neuroprotective Agents
  • SARM1 protein, human