Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth

Cell Rep. 2016 Jul 12;16(2):545-558. doi: 10.1016/j.celrep.2016.06.013. Epub 2016 Jun 30.


Suboptimal axonal regeneration contributes to the consequences of nervous system trauma and neurodegenerative disease, but the intrinsic mechanisms that regulate axon growth remain unclear. We screened 50,400 small molecules for their ability to promote axon outgrowth on inhibitory substrata. The most potent hits were the statins, which stimulated growth of all mouse- and human-patient-derived neurons tested, both in vitro and in vivo, as did combined inhibition of the protein prenylation enzymes farnesyltransferase (PFT) and geranylgeranyl transferase I (PGGT-1). Compensatory sprouting of motor axons may delay clinical onset of amyotrophic lateral sclerosis (ALS). Accordingly, elevated levels of PGGT1B, which would be predicted to reduce sprouting, were found in motor neurons of early- versus late-onset ALS patients postmortem. The mevalonate-prenylation pathway therefore constitutes an endogenous brake on axonal growth, and its inhibition provides a potential therapeutic approach to accelerate neuronal regeneration in humans.

MeSH terms

  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Cell Enlargement
  • Cells, Cultured
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Mevalonic Acid / metabolism
  • Mice
  • Motor Neurons / physiology
  • Nerve Regeneration
  • Neurites / physiology*
  • Protein Prenylation*


  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Mevalonic Acid