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

Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.12.29.522226v1?rss=1
Authors: 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.
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 alpha-Tubulin acetylation. An imbalance in the levels of acetylated alpha-Tubulin has been reported in experimental models of Parkinson's disease (PD) whereas pharmacological or genetic modulation that leads to increased acetylated alpha-Tubulin successfully rescues axonal transport defects and inhibits alpha-Synuclein aggregation. However, the role of acetylation of alpha-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 alpha-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 alpha-Tubulin redistribution to alpha-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 alpha-Synuclein oligomers and are associated with acetylated alpha-Tubulin enriched neurons. In conclusion, we disclose a novel aspect of LB morphogenesis, indicating the role of acetylated alpha-Tubulin in PD, that may provide clues to design novel therapeutic interventions.
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