Acetylated α-Tubulin and α-Synuclein: Physiological Interplay and Contribution to α-Synuclein Oligomerization

Emerging evidence supports that altered a-tubulin acetylation occurs in Parkinson's disease (PD), a neurodegenerative disorder characterized by the deposition of a-synuclein fibrillary aggregates within Lewy bodies and nigrostriatal neuron degeneration. Nevertheless, studies addressing the interplay between a-tubulin acetylation and a-synuclein are lacking. Here, we investigated the relationship between a-synuclein and microtubules in primary midbrain murine neurons and the substantia nigra of post-mortem human brains. Taking advantage of immunofluorescence and Proximity Ligation Assay (PLA), a method allowing us to visualize protein-protein interactions in situ, combined with confocal and super-resolution microscopy, we found that a-synuclein and acetylated a-tubulin colocalized and were in close proximity. Next, we employed an a-synuclein overexpressing cellular model and tested the role of a-tubulin acetylation in a-synuclein oligomer formation. We used the a-tubulin deacetylase HDAC6 inhibitor Tubacin to modulate a-tubulin acetylation, and we evaluated the presence of a-synuclein oligomers by PLA. We found that the increase in acetylated a-tubulin significantly induced a-synuclein oligomerization. In conclusion, we unraveled the link between acetylated a-tubulin and a-synuclein and demonstrated that a-tubulin acetylation could trigger the early step of a-synuclein aggregation. These data suggest that the proper regulation of a-tubulin acetylation might be considered a therapeutic strategy to take on PD.