Linking acetylated alpha-Tubulin redistribution to alpha-Synuclein pathology in brain of Parkinson's disease patients

Mazzetti, S.; Giampietro, F.; Isilgan, H. B.; Calogero, A. M.; Gagliardi, G.; Rolando, C.; Cantele, F. O.; Ascagni, M.; Bramerio, M. A.; Giaccone, G.; Isaias, I. U.; Pezzoli, G.; Cappelletti, G.

doi:10.1101/2022.12.29.522226

bioRxiv · 10.1101/2022.12.29.522226

Linking acetylated alpha-Tubulin redistribution to alpha-Synuclein pathology in brain of Parkinson's disease patients

Mazzetti, S.·Giampietro, F.·Isilgan, H. B.·Calogero, A. M.·Gagliardi, G.·Rolando, C.·Cantele, F. O.·Ascagni, M.·Bramerio, M. A.·Giaccone, G.·Isaias, I. U.·Pezzoli, G.·Cappelletti, G.

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Abstract

Highly specialized microtubules in neurons are crucial to the health and disease of the nervous system, and their properties are strictly regulated by different post-translational modifications, including -Tubulin acetylation. An imbalance in the levels of acetylated -Tubulin has been reported in experimental models of Parkinsons disease (PD) whereas pharmacological or genetic modulation that leads to increased acetylated -Tubulin successfully rescues axonal transport defects and inhibits -Synuclein aggregation. However, the role of acetylation of -Tubulin in the human nervous system is largely unknown as most studies are based on in vitro evidence. To capture the complexity of the pathological processes in vivo, we analysed post-mortem human brain of PD patients and control subjects. In the brain of PD patients at Braak stage 6, we found a redistribution of acetylated -Tubulin, which accumulates in the neuronal cell bodies in subcortical structures but not in the cerebral cortex, and decreases in the axonal compartment, both in the central and peripheral nervous system. High-resolution and 3D reconstruction analysis linked acetylated -Tubulin redistribution to -Synuclein oligomerization, leading us to propose a model for Lewy body (LB) morphogenesis. Finally, for the first time in post-mortem human brain, we observed threadlike structures, resembling tunnelling nanotubes that contain -Synuclein oligomers and are associated with acetylated -Tubulin enriched neurons. In conclusion, we disclose a novel aspect of LB morphogenesis, indicating the role of acetylated -Tubulin in PD, that may provide clues to design novel therapeutic interventions.

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Mazzetti, S., Giampietro, F., Isilgan, H. B., Calogero, A. M., Gagliardi, G., Rolando, C., Cantele, F. O., Ascagni, M., Bramerio, M. A., Giaccone, G., Isaias, I. U., Pezzoli, G., Cappelletti, G.. 2022-12-30. Linking acetylated alpha-Tubulin redistribution to alpha-Synuclein pathology in brain of Parkinson's disease patients. https://doi.org/10.1101/2022.12.29.522226

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