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

• Published in: International journal of molecular sciences 2023-07, Vol.24 (15), p.12287
• Main Authors: Calogero, Alessandra Maria, Basellini, Milo Jarno, Isilgan, Huseyin Berkcan, Longhena, Francesca, Bellucci, Arianna, Mazzetti, Samanta, Rolando, Chiara, Pezzoli, Gianni, Cappelletti, Graziella
• Format: Article
• Language: English
• Subjects: acetylated α-tubulin; alpha-Synuclein; Animals; Antibodies; Brain; Cytoskeleton; Fibroblasts; Humans; Lewy Bodies; Localization; Mice; Microtubules; Nervous system diseases; neurodegeneration; Neurons; Oligomers; Parkinson Disease; Parkinson's disease; Physiological aspects; Physiology; Proteins; Tubacin; Tubulin; Tubulins; α-synuclein
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241512287

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.