Cell Reports (Jul 2016)

Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth

  • Hai Li,
  • Takaaki Kuwajima,
  • Derek Oakley,
  • Elena Nikulina,
  • Jianwei Hou,
  • Wan Seok Yang,
  • Emily Rhodes Lowry,
  • Nuno Jorge Lamas,
  • Mackenzie Weygandt Amoroso,
  • Gist F. Croft,
  • Raghavendra Hosur,
  • Hynek Wichterle,
  • Said Sebti,
  • Marie T. Filbin,
  • Brent Stockwell,
  • Christopher E. Henderson

DOI
https://doi.org/10.1016/j.celrep.2016.06.013
Journal volume & issue
Vol. 16, no. 2
pp. 545 – 558

Abstract

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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.