The Role of Acetylated Microtubules in Mechanosensation in Mice

Abstract

The molecular mechanisms of force transduction in mammalian sensory neurons are largely unexplored. In this project, the effect of Alpha tubulin acetyltransferase 1 (Atat1), an enzyme which acts to imbue microtubules with a highly conserved post- translational modification (PTM) by acetylating the lysine 40 residue of α-tubulin was studied on a behavioural and cellular level. Using a conditional knockout (KO) for Atat1, which specifically removes the enzyme from the peripheral nervous system (PNS), the function of this enzyme, was investigated. It was shown in various behavioural tests that the KO mice show a profound deficit in mechanosensation and nociception. On a cellular level, a strong sub-membrane localization of the acetylated tubulin can be found in around ~ 80% of the wild type DRG cells. There is an absence of this sub-membrane ‘ring’ in DRGs taken from Atat1cKO animals. Thus, we posit that the absence of acetylation causes an increase in microtubule rigidity, which renders the neuronal membrane stiffer in KO mice leading to touch insensitivity. This phenotype can be rescued in cultured DRG cells from the KO background by expression of a plasmid construct which uses an amino acid substitution in tubulin to genetically mimic tubulin acetylation. In light of these results we have recently been exploring options to mimic the KO phenotype in WT DRG cells in vitro, which could provide novel therapeutic strategies for conditions like mechanical allodynia.