Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): 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
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.

Graphical abstract

Teaser

Using a high-throughput phenotypic screen, Li et al. identify statins and inhibitors of protein prenylation as potent neurite-outgrowth-promoting agents. High levels of prenylation enzyme are found in patients with earlier-onset forms of ALS. Prenylation may limit axonal growth in both normal and pathological situations.


from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/297NnvO
via IFTTT