DOI: 10.3390/ijms241512287 ISSN: 1422-0067

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

Alessandra Maria Calogero, Milo Jarno Basellini, Huseyin Berkcan Isilgan, Francesca Longhena, Arianna Bellucci, Samanta Mazzetti, Chiara Rolando, Gianni Pezzoli, Graziella Cappelletti
  • Inorganic Chemistry
  • Organic Chemistry
  • Physical and Theoretical Chemistry
  • Computer Science Applications
  • Spectroscopy
  • Molecular Biology
  • General Medicine
  • Catalysis

Emerging evidence supports that altered α-tubulin acetylation occurs in Parkinson’s disease (PD), a neurodegenerative disorder characterized by the deposition of α-synuclein fibrillary aggregates within Lewy bodies and nigrostriatal neuron degeneration. Nevertheless, studies addressing the interplay between α-tubulin acetylation and α-synuclein are lacking. Here, we investigated the relationship between α-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 α-synuclein and acetylated α-tubulin colocalized and were in close proximity. Next, we employed an α-synuclein overexpressing cellular model and tested the role of α-tubulin acetylation in α-synuclein oligomer formation. We used the α-tubulin deacetylase HDAC6 inhibitor Tubacin to modulate α-tubulin acetylation, and we evaluated the presence of α-synuclein oligomers by PLA. We found that the increase in acetylated α-tubulin significantly induced α-synuclein oligomerization. In conclusion, we unraveled the link between acetylated α-tubulin and α-synuclein and demonstrated that α-tubulin acetylation could trigger the early step of α-synuclein aggregation. These data suggest that the proper regulation of α-tubulin acetylation might be considered a therapeutic strategy to take on PD.

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