Modulating microtubule stability via α-tubulin acetylation partially restores Golgi fragmentation in spinal muscular atrophy

Background/aim: Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by the loss of survival of motor neuron (SMN) protein. SMN deficiency leads to perturbations of the cytoskeleton, including microtubules, which are mainly involved in motility-related cellular processes. However, the molecular mechanisms of microtubule dysregulation in SMA remain elusive. Alpha (α)-tubulin is a structural component of microtubules, and its posttranslational modifications affect microtubule dynamics. Here, we aimed to investigate α-tubulin acetylation and related molecular mechanisms in SMA. Materials and methods: model and patient-derived fibroblasts, were used in the study. Western blot and quantitative microscopic analysis were performed to analyze α-tubulin acetylation and related mechanisms. Results: model and in SMA patient fibroblast cells but not in mouse models. This decrease in acetylation is associated with upregulation of the major tubulin deacetylase, HDAC6, in patient cells compared with healthy controls. Microtubules play a role in the organization of the Golgi apparatus, and we demonstrated that increasing α-tubulin acetylation by pharmacological inhibition of HDAC6 partially restored the fragmented morphology of the Golgi apparatus in SMA. Conclusion: Our findings provide new insight into the molecular basis of SMA, indicating that cellular pathologies, including abnormal Golgi morphology, are associated with microtubule dysregulations caused by altered α-tubulin posttranslational modifications and regulatory proteins. Our findings support that microtubule perturbations are part of SMA pathology.