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

Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth.

Author information

1
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.
2
Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA.
3
Department of Biological Sciences, Hunter College, City University of New York, NY 10065, USA.
4
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.
5
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.
6
Computational Biology, Biogen Inc., Cambridge, MA 02142, USA.
7
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.
8
Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA.
9
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.

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.

PMID:
27373155
DOI:
10.1016/j.celrep.2016.06.013
[Indexed for MEDLINE]
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