Synaptic branch stability is mediated by non-enzymatic functions of MEC-17/αTAT1 and ATAT-2

Abstract

Microtubules are fundamental elements of neuronal structure and function. They are dynamic structures formed from protofilament chains of α- and β-tubulin heterodimers. Acetylation of the lysine 40 (K40) residue of α-tubulin protects microtubules from mechanical stresses by imparting structural elasticity. The enzyme responsible for this acetylation event is MEC-17/αTAT1. Despite its functional importance, however, the consequences of altered MEC-17/αTAT1 levels on neuronal structure and function are incompletely defined. Here we demonstrate that overexpression or loss of MEC-17, or of its functional paralogue ATAT-2, causes a delay in synaptic branch extension, and defective synaptogenesis in the mechanosensory neurons of Caenorhabditis elegans. Strikingly, by adulthood, the synaptic branches in these animals are lost, while the main axon shaft remains mostly intact. We show that MEC-17 and ATAT-2 regulate the stability of the synaptic branches largely independently from their acetyltransferase domains. Genetic analyses reveals novel interactions between both mec-17 and atat-2 with the focal adhesion gene zyx-1/Zyxin, which has previously been implicated in actin remodelling. Together, our results reveal new, acetylation-independent roles for MEC-17 and ATAT-2 in the development and maintenance of neuronal architecture.

Nano-pulling stimulates axon regeneration in dorsal root ganglia by inducing stabilization of axonal microtubules and activation of local translation

“…Conversely, this ratio was found to increase in the shaft of stretched axons, highlighting the presence of more stable MTs ( Takemura et al, 1992 ; Cappelletti et al, 2021 ). A correlation between the acetylation of MTs and their stabilization has always been observed in various studies on neurons ( Morley et al, 2016 ; Yan et al, 2018 ; Teoh et al, 2022 ), as well as in other studies on non-neuronal models ( Swiatlowska et al, 2020 ; Coleman et al, 2021 ). Consistently, in previous works we found that the force-induced stabilization of the MTs in the shaft causes their accumulation in stretched axons ( De Vincentiis et al, 2020 , 2023 ; Falconieri et al, 2023b ).…”

Nano-pulling stimulates axon regeneration in dorsal root ganglia by inducing stabilization of axonal microtubules and activation of local translation

“…Conversely, this ratio was found to increase in the shaft of stretched axons, documenting the presence of more stable MTs (Takemura et al, 1992; Cappelletti et al, 2021). In general, an increase in acetylation of MTs, with a consequent increase in stability, has been always observed in various studies on neurons (Morley et al, 2016; Yan et al, 2018; Teoh et al, 2022), as well as in other work on non-neuronal models (Swiatlowska et al, 2020; Coleman et al, 2021). We found in previous works that the stabilization of the MTs in the shaft causes their accumulation in the axon (De Vincentiis et al, 2020, 2023; Falconieri et al, 2023).…”

Microtubule acetylation dyshomeostasis in Parkinson’s disease

“…Optimum levels of MEC-17 and ATAT-2 are needed for the temporal control of synaptic branching. Overexpression or loss of these enzymes causes a delay in synaptic branching and impaired synaptic formation in mechanosensory neurons of Caenorhabditis elegans [ 141 ]. Neuronal cells with defective elongators show a drastic reduction of acetylated α-tubulin.…”

“…Biochemical analyses of tubulin deacetylation via HDAC6 revealed its strong preference for tubulin dimers to assemble MTs. Although HDAC6 is believed to deacetylate the K40 residue of α-tubulin, quantitative mass spectrometry studies revealed K60, K370, and K394 on α-tubulin as well as K58, K103, and K154 on β-tubulin as newer putative sites of HDAC6-mediated deacetylation [ 141 ]. A previous study showed that increased MT acetylation via HDAC6 inhibition leads to the recruitment of molecular motors kinesin-1 and cytoplasmic dynein to MTs, thereby increasing the MT-dependent corticostriatal transport of BDNF [ 137 ].…”