Cargando…

α-Tubulin Acetyltransferase Is a Novel Target Mediating Neurite Growth Inhibitory Effects of Chondroitin Sulfate Proteoglycans and Myelin-Associated Glycoprotein

Damage to the CNS results in neuronal and axonal degeneration, and subsequent neurological dysfunction. Endogenous repair in the CNS is impeded by inhibitory chemical and physical barriers, such as chondroitin sulfate proteoglycans (CSPGs) and myelin-associated glycoprotein (MAG), which prevent axon...

Descripción completa

Detalles Bibliográficos
Autores principales: Wong, Victor S. C., Picci, Cristina, Swift, Michelle, Levinson, Max, Willis, Dianna, Langley, Brett
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830348/
https://www.ncbi.nlm.nih.gov/pubmed/29497702
http://dx.doi.org/10.1523/ENEURO.0240-17.2018
_version_ 1783302980964974592
author Wong, Victor S. C.
Picci, Cristina
Swift, Michelle
Levinson, Max
Willis, Dianna
Langley, Brett
author_facet Wong, Victor S. C.
Picci, Cristina
Swift, Michelle
Levinson, Max
Willis, Dianna
Langley, Brett
author_sort Wong, Victor S. C.
collection PubMed
description Damage to the CNS results in neuronal and axonal degeneration, and subsequent neurological dysfunction. Endogenous repair in the CNS is impeded by inhibitory chemical and physical barriers, such as chondroitin sulfate proteoglycans (CSPGs) and myelin-associated glycoprotein (MAG), which prevent axon regeneration. Previously, it has been demonstrated that the inhibition of axonal histone deacetylase-6 (HDAC6) can promote microtubule α-tubulin acetylation and restore the growth of CSPGs- and MAG-inhibited axons. Since the acetylation of α-tubulin is regulated by two opposing enzymes, HDAC6 (deacetylation) and α-tubulin acetyltransferase-1 (αTAT1; acetylation), we have investigated the regulation of these enzymes downstream of a growth inhibitory signal. Our findings show that exposure of primary mouse cortical neurons to soluble CSPGs and MAG substrates cause an acute and RhoA-kinase-dependent reduction in α-tubulin acetylation and αTAT1 protein levels, without changes to either HDAC6 levels or HDAC6 activity. The CSPGs- and MAG-induced reduction in αTAT1 occurs primarily in the distal and middle regions of neurites and reconstitution of αTAT1, either by Rho-associated kinase (ROCK) inhibition or lentiviral-mediated αTAT1 overexpression, can restore neurite growth. Lastly, we demonstrate that CSPGs and MAG signaling decreases αTAT1 levels posttranscriptionally via a ROCK-dependent increase in αTAT1 protein turnover. Together, these findings define αTAT1 as a novel potential therapeutic target for ameliorating CNS injury characterized by growth inhibitory substrates that are prohibitive to axonal regeneration.
format Online
Article
Text
id pubmed-5830348
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Society for Neuroscience
record_format MEDLINE/PubMed
spelling pubmed-58303482018-03-01 α-Tubulin Acetyltransferase Is a Novel Target Mediating Neurite Growth Inhibitory Effects of Chondroitin Sulfate Proteoglycans and Myelin-Associated Glycoprotein Wong, Victor S. C. Picci, Cristina Swift, Michelle Levinson, Max Willis, Dianna Langley, Brett eNeuro New Research Damage to the CNS results in neuronal and axonal degeneration, and subsequent neurological dysfunction. Endogenous repair in the CNS is impeded by inhibitory chemical and physical barriers, such as chondroitin sulfate proteoglycans (CSPGs) and myelin-associated glycoprotein (MAG), which prevent axon regeneration. Previously, it has been demonstrated that the inhibition of axonal histone deacetylase-6 (HDAC6) can promote microtubule α-tubulin acetylation and restore the growth of CSPGs- and MAG-inhibited axons. Since the acetylation of α-tubulin is regulated by two opposing enzymes, HDAC6 (deacetylation) and α-tubulin acetyltransferase-1 (αTAT1; acetylation), we have investigated the regulation of these enzymes downstream of a growth inhibitory signal. Our findings show that exposure of primary mouse cortical neurons to soluble CSPGs and MAG substrates cause an acute and RhoA-kinase-dependent reduction in α-tubulin acetylation and αTAT1 protein levels, without changes to either HDAC6 levels or HDAC6 activity. The CSPGs- and MAG-induced reduction in αTAT1 occurs primarily in the distal and middle regions of neurites and reconstitution of αTAT1, either by Rho-associated kinase (ROCK) inhibition or lentiviral-mediated αTAT1 overexpression, can restore neurite growth. Lastly, we demonstrate that CSPGs and MAG signaling decreases αTAT1 levels posttranscriptionally via a ROCK-dependent increase in αTAT1 protein turnover. Together, these findings define αTAT1 as a novel potential therapeutic target for ameliorating CNS injury characterized by growth inhibitory substrates that are prohibitive to axonal regeneration. Society for Neuroscience 2018-02-28 /pmc/articles/PMC5830348/ /pubmed/29497702 http://dx.doi.org/10.1523/ENEURO.0240-17.2018 Text en Copyright © 2018 Wong et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle New Research
Wong, Victor S. C.
Picci, Cristina
Swift, Michelle
Levinson, Max
Willis, Dianna
Langley, Brett
α-Tubulin Acetyltransferase Is a Novel Target Mediating Neurite Growth Inhibitory Effects of Chondroitin Sulfate Proteoglycans and Myelin-Associated Glycoprotein
title α-Tubulin Acetyltransferase Is a Novel Target Mediating Neurite Growth Inhibitory Effects of Chondroitin Sulfate Proteoglycans and Myelin-Associated Glycoprotein
title_full α-Tubulin Acetyltransferase Is a Novel Target Mediating Neurite Growth Inhibitory Effects of Chondroitin Sulfate Proteoglycans and Myelin-Associated Glycoprotein
title_fullStr α-Tubulin Acetyltransferase Is a Novel Target Mediating Neurite Growth Inhibitory Effects of Chondroitin Sulfate Proteoglycans and Myelin-Associated Glycoprotein
title_full_unstemmed α-Tubulin Acetyltransferase Is a Novel Target Mediating Neurite Growth Inhibitory Effects of Chondroitin Sulfate Proteoglycans and Myelin-Associated Glycoprotein
title_short α-Tubulin Acetyltransferase Is a Novel Target Mediating Neurite Growth Inhibitory Effects of Chondroitin Sulfate Proteoglycans and Myelin-Associated Glycoprotein
title_sort α-tubulin acetyltransferase is a novel target mediating neurite growth inhibitory effects of chondroitin sulfate proteoglycans and myelin-associated glycoprotein
topic New Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830348/
https://www.ncbi.nlm.nih.gov/pubmed/29497702
http://dx.doi.org/10.1523/ENEURO.0240-17.2018
work_keys_str_mv AT wongvictorsc atubulinacetyltransferaseisanoveltargetmediatingneuritegrowthinhibitoryeffectsofchondroitinsulfateproteoglycansandmyelinassociatedglycoprotein
AT piccicristina atubulinacetyltransferaseisanoveltargetmediatingneuritegrowthinhibitoryeffectsofchondroitinsulfateproteoglycansandmyelinassociatedglycoprotein
AT swiftmichelle atubulinacetyltransferaseisanoveltargetmediatingneuritegrowthinhibitoryeffectsofchondroitinsulfateproteoglycansandmyelinassociatedglycoprotein
AT levinsonmax atubulinacetyltransferaseisanoveltargetmediatingneuritegrowthinhibitoryeffectsofchondroitinsulfateproteoglycansandmyelinassociatedglycoprotein
AT willisdianna atubulinacetyltransferaseisanoveltargetmediatingneuritegrowthinhibitoryeffectsofchondroitinsulfateproteoglycansandmyelinassociatedglycoprotein
AT langleybrett atubulinacetyltransferaseisanoveltargetmediatingneuritegrowthinhibitoryeffectsofchondroitinsulfateproteoglycansandmyelinassociatedglycoprotein