Inhibiting poly(ADP-ribosylation) improves axon regeneration

Elife. 2016 Oct 4:5:e12734. doi: 10.7554/eLife.12734.

Abstract

The ability of a neuron to regenerate its axon after injury depends in part on its intrinsic regenerative potential. Here, we identify novel intrinsic regulators of axon regeneration: poly(ADP-ribose) glycohodrolases (PARGs) and poly(ADP-ribose) polymerases (PARPs). PARGs, which remove poly(ADP-ribose) from proteins, act in injured C. elegans GABA motor neurons to enhance axon regeneration. PARG expression is regulated by DLK signaling, and PARGs mediate DLK function in enhancing axon regeneration. Conversely, PARPs, which add poly(ADP-ribose) to proteins, inhibit axon regeneration of both C. elegans GABA neurons and mammalian cortical neurons. Furthermore, chemical PARP inhibitors improve axon regeneration when administered after injury. Our results indicate that regulation of poly(ADP-ribose) levels is a critical function of the DLK regeneration pathway, that poly-(ADP ribosylation) inhibits axon regeneration across species, and that chemical inhibition of PARPs can elicit axon regeneration.

Keywords: C. elegans; axon regeneration; dlk-1/MAPKKK; mouse; neuroscience; poly(ADP-ribose) glycohydrolase; poly(ADP-ribose) polymerase.

Publication types

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

MeSH terms

  • ADP Ribose Transferases / metabolism*
  • Animals
  • Axons / physiology*
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans / physiology
  • Glycoside Hydrolases / metabolism*
  • Poly ADP Ribosylation*
  • Regeneration*

Substances

  • ADP Ribose Transferases
  • Glycoside Hydrolases
  • poly ADP-ribose glycohydrolase