ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation

Nat Cell Biol. 2011 Nov 6;13(12):1415-23. doi: 10.1038/ncb2373.


Wallerian degeneration is observed in many neurological disorders, and it is therefore important to elucidate the axonal degeneration mechanism to prevent, and further develop treatment for, such diseases. The ubiquitin-proteasome system (UPS) has been implicated in Wallerian degeneration, but the underlying molecular mechanism remains unclear. Here we show that ZNRF1, an E3 ligase, promotes Wallerian degeneration by targeting AKT to degrade through the UPS. AKT phosphorylates glycogen synthase kinase-3β (GSK3B), and thereby inactivates it in axons. AKT overexpression significantly delays axonal degeneration. Overexpression of the active (non-phosphorylated) form of GSK3B induces CRMP2 phosphorylation, which is required for the microtubule reorganization observed in the degenerating axon. The inhibition of GSK3B and the overexpression of non-phosphorylated CRMP2 both protected axons from Wallerian degeneration. These findings indicate that the ZNRF1-AKT-GSK3B-CRMP2 pathway plays an important role in controlling Wallerian degeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / enzymology
  • Axons / metabolism
  • Cells, Cultured
  • Female
  • Glycogen Synthase Kinase 3 / physiology*
  • Glycogen Synthase Kinase 3 beta
  • HEK293 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Nerve Tissue Proteins / metabolism*
  • Phosphorylation / physiology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / physiology
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitin-Protein Ligases / physiology*
  • Wallerian Degeneration / metabolism*


  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • collapsin response mediator protein-2
  • Ubiquitin-Protein Ligases
  • ZNRF1 protein, mouse
  • Akt1 protein, mouse
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3