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

PUBLICATION: 
Journal Article
Authors: 
Wong VSC, Picci C, Swift M, Levinson M, Willis D, Langley B
Year Published: 
2018
Publisher: 
eNeuro. 2018 Feb 28;5(1). pii: ENEURO.0240-17.2018. doi: 10.1523/ENEURO.0240-17.2018. eCollection 2018 Jan-Feb.
Identifiers: 
PMID: 29497702 | PMCID: PMC5830348 | DOI: 10.1523/ENEURO.0240-17.2018
Full-Text on Pubmed

Abstract

Damage to the central nervous system (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 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 ROCK inhibition or lentiviral-mediated αTAT1 overexpression, can restore neurite growth. Lastly, we demonstrate that CSPGs and MAG signaling decreases αTAT1 levels post-transcriptionally 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.

Significant Statement 

Chondroitin sulfate proteoglycans (CSPGs) and myelin-associated glycoprotein (MAG) represent significant barriers to axon regeneration after central nervous system (CNS) injury. Inhibition of axonal histone deacetylase-6 (HDAC6), an enzyme that regulates α-tubulin deacetylation, has been shown to overcome the inhibitory effects of CSPGs and MAG to axon growth. In the present study, we report that αTAT1, the α-tubulin acetyltransferase that opposes HDAC6’s activity, is downregulated in neurites by CSPGs and MAG in cortical neurons, in vitro. This reduction is associated with a loss of α-tubulin acetylation and occurs via a RhoA-kinase-dependent pathway. Restoring αTAT1 expression in CSPGs- or MAG-inhibited cortical neurons rescues neurite growth. Our results suggest that αTAT1 is a potential therapeutic target to promote axonal regeneration in the CNS.

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