Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Outros Autores: | , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/1822/50999 |
Resumo: | 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. |
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Protein Prenylation Constitutes an Endogenous Brake on Axonal GrowthCiências Médicas::Medicina BásicaScience & TechnologySuboptimal 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.Samaher Fageiry and Cyndel Vollmer for help with the culture model, Kevin Eggan and collaborators for kindly providing Hb9::GFP human ESC reporter lines, and Chuck Karan and members of the High-Throughput Screening and Chemistry Shared Facility for support and technical guidance. We thank the He lab (Harvard) for training in optic nerve crush. We are grateful to members of the Project A.L.S., Henderson, Wichterle, and Stockwell laboratories at Columbia University for much help and continuous critical discussion. We thank our Biogen colleagues Alex McCampbell, Sha Mi, and Richard Ransohoff for critical reading of the manuscript. This work received invaluable support from the New York State Spinal Cord Injury Research Board (NYS-SCIRB C020923), P2ALS, Target ALS, the Tow Foundation, the SMA Foundation, Project A.L.S., NYSTEM (C026715), The Helmsley Charitable Trust, NINDS R01-NS056422 and NS072428, and the Columbia MD-PhD program. Brent R. Stockwell is an Early Career Scientist of the Howard Hughes Medical Institute, and this research was additionally funded by the NIH (5R01CA097061 and R01CA161061, to B.S.) and New York State Stem Cell Science (C026715)info:eu-repo/semantics/publishedVersionElsevierUniversidade do MinhoLi, HaiKuwajima,TakaakiOakley, DerekNikulina, ElenaHou, JianweiYang, Wan SeokLowry, Emily RhodesLamas, Nuno JorgeAmoroso, Mackenzie WeygandtCroft, Gist F.et. al.2016-07-132016-07-13T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/50999engLi, H., Kuwajima, T., Oakley, D., Nikulina, E., Hou, J., Yang, W. S., ... & Hosur, R. (2016). Protein prenylation constitutes an endogenous brake on axonal growth. Cell reports, 16(2), 545-5582211-124710.1016/j.celrep.2016.06.01327373155https://www.sciencedirect.com/science/article/pii/S2211124716307379info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:23:30Zoai:repositorium.sdum.uminho.pt:1822/50999Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:17:13.949077Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth |
title |
Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth |
spellingShingle |
Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth Li, Hai Ciências Médicas::Medicina Básica Science & Technology |
title_short |
Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth |
title_full |
Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth |
title_fullStr |
Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth |
title_full_unstemmed |
Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth |
title_sort |
Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth |
author |
Li, Hai |
author_facet |
Li, Hai Kuwajima,Takaaki Oakley, Derek Nikulina, Elena Hou, Jianwei Yang, Wan Seok Lowry, Emily Rhodes Lamas, Nuno Jorge Amoroso, Mackenzie Weygandt Croft, Gist F. et. al. |
author_role |
author |
author2 |
Kuwajima,Takaaki Oakley, Derek Nikulina, Elena Hou, Jianwei Yang, Wan Seok Lowry, Emily Rhodes Lamas, Nuno Jorge Amoroso, Mackenzie Weygandt Croft, Gist F. et. al. |
author2_role |
author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Li, Hai Kuwajima,Takaaki Oakley, Derek Nikulina, Elena Hou, Jianwei Yang, Wan Seok Lowry, Emily Rhodes Lamas, Nuno Jorge Amoroso, Mackenzie Weygandt Croft, Gist F. et. al. |
dc.subject.por.fl_str_mv |
Ciências Médicas::Medicina Básica Science & Technology |
topic |
Ciências Médicas::Medicina Básica Science & Technology |
description |
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. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-07-13 2016-07-13T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/50999 |
url |
http://hdl.handle.net/1822/50999 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Li, H., Kuwajima, T., Oakley, D., Nikulina, E., Hou, J., Yang, W. S., ... & Hosur, R. (2016). Protein prenylation constitutes an endogenous brake on axonal growth. Cell reports, 16(2), 545-558 2211-1247 10.1016/j.celrep.2016.06.013 27373155 https://www.sciencedirect.com/science/article/pii/S2211124716307379 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Elsevier |
publisher.none.fl_str_mv |
Elsevier |
dc.source.none.fl_str_mv |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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