Neuronally Enriched RUFY3 Is Required for Caspase-Mediated Axon Degeneration

Neuron. 2019 Aug 7;103(3):412-422.e4. doi: 10.1016/j.neuron.2019.05.030. Epub 2019 Jun 17.


Selective synaptic and axonal degeneration are critical aspects of both brain development and neurodegenerative disease. Inhibition of caspase signaling in neurons is a potential therapeutic strategy for neurodegenerative disease, but no neuron-specific modulators of caspase signaling have been described. Using a mass spectrometry approach, we discovered that RUFY3, a neuronally enriched protein, is essential for caspase-mediated degeneration of TRKA+ sensory axons in vitro and in vivo. Deletion of Rufy3 protects axons from degeneration, even in the presence of activated CASP3 that is competent to cleave endogenous substrates. Dephosphorylation of RUFY3 at residue S34 appears required for axon degeneration, providing a potential mechanism for neurons to locally control caspase-driven degeneration. Neuronally enriched RUFY3 thus provides an entry point for understanding non-apoptotic functions of CASP3 and a potential target to modulate caspase signaling specifically in neurons for neurodegenerative disease.

Keywords: axon degeneration; caspase signaling; chemical biology; degradomics; mass spectrometry; neurodegeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / enzymology
  • Axons / pathology*
  • Caspase 3 / physiology
  • Cells, Cultured
  • Cytoskeletal Proteins
  • Enzyme Activation
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / embryology
  • Mice
  • Mice, Knockout
  • Nerve Degeneration / enzymology
  • Nerve Degeneration / pathology*
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / physiology*
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Receptor, trkA / physiology
  • Sensory Receptor Cells / physiology
  • Structure-Activity Relationship


  • Cytoskeletal Proteins
  • Nerve Tissue Proteins
  • Rufy3 protein, mouse
  • Receptor, trkA
  • Casp3 protein, mouse
  • Caspase 3