Wallerian Degeneration Is Executed by an NMN-SARM1-Dependent Late Ca(2+) Influx but Only Modestly Influenced by Mitochondria

Cell Rep. 2015 Dec 22;13(11):2539-2552. doi: 10.1016/j.celrep.2015.11.032. Epub 2015 Dec 10.


Axon injury leads to rapid depletion of NAD-biosynthetic enzyme NMNAT2 and high levels of its substrate, NMN. We proposed a key role for NMN in Wallerian degeneration but downstream events and their relationship to other mediators remain unclear. Here, we show, in vitro and in vivo, that axotomy leads to a late increase in intra-axonal Ca(2+), abolished by pharmacological or genetic reduction of NMN levels. NMN requires the pro-degenerative protein SARM1 to stimulate Ca(2+) influx and axon degeneration. While inhibition of NMN synthesis and SARM1 deletion block Ca(2+) rise and preserve axonal integrity, they fail to prevent early mitochondrial dynamic changes. Furthermore, depolarizing mitochondria does not alter the rate of Wallerian degeneration. These data reveal that NMN and SARM1 act in a common pathway culminating in intra-axonal Ca(2+) increase and fragmentation and dissociate mitochondrial dysfunctions from this pathway, elucidating which steps may be most effective as targets for therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / pharmacology
  • Amidohydrolases / metabolism
  • Animals
  • Armadillo Domain Proteins / deficiency
  • Armadillo Domain Proteins / genetics*
  • Axons / drug effects
  • Axons / metabolism
  • Calcium / metabolism*
  • Cytoskeletal Proteins / deficiency
  • Cytoskeletal Proteins / genetics*
  • Ions / chemistry
  • Ions / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Nicotinamide Mononucleotide / metabolism*
  • Nicotinamide Mononucleotide / pharmacology
  • Nicotinamide-Nucleotide Adenylyltransferase / metabolism
  • Piperidines / pharmacology
  • Wallerian Degeneration / pathology


  • Acrylamides
  • Armadillo Domain Proteins
  • Cytoskeletal Proteins
  • Ions
  • N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
  • Piperidines
  • SARM1 protein, mouse
  • Nicotinamide Mononucleotide
  • Nicotinamide-Nucleotide Adenylyltransferase
  • Nmnat2 protein, mouse
  • Amidohydrolases
  • nicotinamidenucleotide amidase
  • Calcium