Linking acetylated α-Tubulin redistribution to α-Synuclein pathology in brain of Parkinson’s disease patients
Abstract Highly specialized microtubules in neurons are crucial to both health and disease of the nervous system, and their properties are strictly regulated by different post-translational modifications, including α-Tubulin acetylation. An imbalance in the levels of acetylated α-Tubulin has been re...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-023-00607-9 |
| _version_ | 1827388701563420672 |
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| author | Samanta Mazzetti Federica Giampietro Alessandra Maria Calogero Huseyin Berkcan Isilgan Gloria Gagliardi Chiara Rolando Francesca Cantele Miriam Ascagni Manuela Bramerio Giorgio Giaccone Ioannis Ugo Isaias Gianni Pezzoli Graziella Cappelletti |
| author_facet | Samanta Mazzetti Federica Giampietro Alessandra Maria Calogero Huseyin Berkcan Isilgan Gloria Gagliardi Chiara Rolando Francesca Cantele Miriam Ascagni Manuela Bramerio Giorgio Giaccone Ioannis Ugo Isaias Gianni Pezzoli Graziella Cappelletti |
| author_sort | Samanta Mazzetti |
| collection | DOAJ |
| description | Abstract Highly specialized microtubules in neurons are crucial to both health and disease of the nervous system, and their properties are strictly regulated by different post-translational modifications, including α-Tubulin acetylation. An imbalance in the levels of acetylated α-Tubulin has been reported in experimental models of Parkinson’s disease (PD) whereas pharmacological or genetic modulation that leads to increased acetylated α-Tubulin successfully rescues axonal transport defects and inhibits α-Synuclein aggregation. However, the role of acetylation of α-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 α-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 putamen bundles of fibres and in sudomotor fibres. High-resolution and 3D reconstruction analysis linked acetylated α-Tubulin redistribution to α-Synuclein oligomerization and to phosphorylated Ser 129 α-Synuclein, leading us to propose a model for Lewy body (LB) formation. Finally, in post-mortem human brain, we observed threadlike structures, resembling tunnelling nanotubes that contain α-Synuclein oligomers and are associated with acetylated α-Tubulin enriched neurons. In conclusion, we support the role of acetylated α-Tubulin in PD pathogenesis and LB formation. |
| first_indexed | 2024-03-08T16:22:43Z |
| format | Article |
| id | doaj.art-ca64ae35c99a45449e10f133fad7079d |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-08T16:22:43Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-ca64ae35c99a45449e10f133fad7079d2024-01-07T12:17:08ZengNature Portfolionpj Parkinson's Disease2373-80572024-01-0110111510.1038/s41531-023-00607-9Linking acetylated α-Tubulin redistribution to α-Synuclein pathology in brain of Parkinson’s disease patientsSamanta Mazzetti0Federica Giampietro1Alessandra Maria Calogero2Huseyin Berkcan Isilgan3Gloria Gagliardi4Chiara Rolando5Francesca Cantele6Miriam Ascagni7Manuela Bramerio8Giorgio Giaccone9Ioannis Ugo Isaias10Gianni Pezzoli11Graziella Cappelletti12Department of Biosciences, Università degli Studi di MilanoDepartment of Biosciences, Università degli Studi di MilanoDepartment of Biosciences, Università degli Studi di MilanoDepartment of Biosciences, Università degli Studi di MilanoDepartment of Biosciences, Università degli Studi di MilanoDepartment of Biosciences, Università degli Studi di MilanoDepartment of Chemistry, Università degli Studi di MilanoUnitech NOLIMITS, Università degli Studi di MilanoS. C. Divisione Oncologia Falck and S. C. Divisione Anatomia Patologica, Ospedale Niguarda Ca’ GrandaUnit of Neuropathology and Neurology, Fondazione IRCCS Istituto Neurologico Carlo BestaParkinson Institute, ASST G. Pini-CTO, MilanFondazione Grigioni per il Morbo di ParkinsonDepartment of Biosciences, Università degli Studi di MilanoAbstract Highly specialized microtubules in neurons are crucial to both health and disease of the nervous system, and their properties are strictly regulated by different post-translational modifications, including α-Tubulin acetylation. An imbalance in the levels of acetylated α-Tubulin has been reported in experimental models of Parkinson’s disease (PD) whereas pharmacological or genetic modulation that leads to increased acetylated α-Tubulin successfully rescues axonal transport defects and inhibits α-Synuclein aggregation. However, the role of acetylation of α-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 α-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 putamen bundles of fibres and in sudomotor fibres. High-resolution and 3D reconstruction analysis linked acetylated α-Tubulin redistribution to α-Synuclein oligomerization and to phosphorylated Ser 129 α-Synuclein, leading us to propose a model for Lewy body (LB) formation. Finally, in post-mortem human brain, we observed threadlike structures, resembling tunnelling nanotubes that contain α-Synuclein oligomers and are associated with acetylated α-Tubulin enriched neurons. In conclusion, we support the role of acetylated α-Tubulin in PD pathogenesis and LB formation.https://doi.org/10.1038/s41531-023-00607-9 |
| spellingShingle | Samanta Mazzetti Federica Giampietro Alessandra Maria Calogero Huseyin Berkcan Isilgan Gloria Gagliardi Chiara Rolando Francesca Cantele Miriam Ascagni Manuela Bramerio Giorgio Giaccone Ioannis Ugo Isaias Gianni Pezzoli Graziella Cappelletti Linking acetylated α-Tubulin redistribution to α-Synuclein pathology in brain of Parkinson’s disease patients npj Parkinson's Disease |
| title | Linking acetylated α-Tubulin redistribution to α-Synuclein pathology in brain of Parkinson’s disease patients |
| title_full | Linking acetylated α-Tubulin redistribution to α-Synuclein pathology in brain of Parkinson’s disease patients |
| title_fullStr | Linking acetylated α-Tubulin redistribution to α-Synuclein pathology in brain of Parkinson’s disease patients |
| title_full_unstemmed | Linking acetylated α-Tubulin redistribution to α-Synuclein pathology in brain of Parkinson’s disease patients |
| title_short | Linking acetylated α-Tubulin redistribution to α-Synuclein pathology in brain of Parkinson’s disease patients |
| title_sort | linking acetylated α tubulin redistribution to α synuclein pathology in brain of parkinson s disease patients |
| url | https://doi.org/10.1038/s41531-023-00607-9 |
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