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
Affiliations
Hai Li
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
Takaaki Kuwajima
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
Derek Oakley
Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA
Elena Nikulina
Department of Biological Sciences, Hunter College, City University of New York, NY 10065, USA
Jianwei Hou
Department of Biological Sciences, Hunter College, City University of New York, NY 10065, USA
Wan Seok Yang
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
Emily Rhodes Lowry
Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA
Nuno Jorge Lamas
Department of Pathology and Cell Biology, Neurology, and Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Mackenzie Weygandt Amoroso
Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA
Gist F. Croft
Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA
Raghavendra Hosur
Computational Biology, Biogen Inc., Cambridge, MA 02142, USA
Hynek Wichterle
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
Said Sebti
Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA
Marie T. Filbin
Department of Biological Sciences, Hunter College, City University of New York, NY 10065, USA
Brent Stockwell
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
Christopher E. Henderson
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
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.
