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 á-tubulin acetylation and restore the growth of CSPGs- and MAG-inhibited axons. Since the acetylation of á-tubulin is regulated by two opposing enzymes, HDAC6 (deacetylation) and á-tubulin acetyltransferase-1 (áTAT1; 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 á-tubulin acetylation and áTAT1 protein levels, without changes to either HDAC6 levels or HDAC6 activity. The CSPGs- and MAG-induced reduction in áTAT1 occurs primarily in the distal and middle regions of neurites and reconstitution of áTAT1, either by Rho-associated kinase (ROCK) inhibition or lentiviral-mediated áTAT1 overexpression, can restore neurite growth. Lastly, we demonstrate that CSPGs and MAG signaling decreases áTAT1 levels posttranscriptionally via a ROCK-dependent increase in áTAT1 protein turnover. Together, these findings define áTAT1 as a novel potential therapeutic target for ameliorating CNS injury characterized by growth inhibitory substrates that are prohibitive to axonal regeneration.
Acetyltransferases Animals