title: Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth.
abstract: 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.
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Neurology, and Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Li
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Neurology, and Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kuwajima
authors.affiliation: Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Oakley
authors.affiliation: Department of Biological Sciences, Hunter College, City University of New York, NY 10065, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Nikulina
authors.affiliation: Department of Biological Sciences, Hunter College, City University of New York, NY 10065, USA.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Hou
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA; Howard Hughes Medical Institute and Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY 10027, USA.
authors.forename: Wan Seok
authors.initials: WS
authors.lastname: Yang
authors.affiliation: Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA.
authors.forename: Emily Rhodes
authors.initials: ER
authors.lastname: Lowry
authors.affiliation: Department of Pathology and Cell Biology, Neurology, and Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA; Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, 4710-057 Braga, Minho, Portugal.
authors.forename: Nuno Jorge
authors.initials: NJ
authors.lastname: Lamas
authors.affiliation: Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA.
authors.forename: Mackenzie Weygandt
authors.initials: MW
authors.lastname: Amoroso
authors.affiliation: Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA.
authors.forename: Gist F
authors.initials: GF
authors.lastname: Croft
authors.affiliation: Computational Biology, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Hosur
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Neurology, and Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA.
authors.forename: Hynek
authors.initials: H
authors.lastname: Wichterle
authors.affiliation: Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Said
authors.initials: S
authors.lastname: Sebti
authors.affiliation: Department of Biological Sciences, Hunter College, City University of New York, NY 10065, USA.
authors.forename: Marie T
authors.initials: MT
authors.lastname: Filbin
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA; Howard Hughes Medical Institute and Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY 10027, USA.
authors.forename: Brent
authors.initials: B
authors.lastname: Stockwell
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA; Department of Rehabilitation and Regenerative Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Neurology, and Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA; Target ALS Foundation, New York, NY 10032, USA. Electronic address: chris.henderson@biogen.com.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Henderson
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology; D000818:Animals; D049108:Cell Enlargement; D002478:Cells, Cultured; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D009046:Motor Neurons / Q000502:physiology; D009416:Nerve Regeneration; D016501:Neurites / Q000502:physiology*; D017368:Protein Prenylation
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008798:Mevalonic Acid