Linking acetylated α-Tubulin redistribution to α-Synuclein pathology in brain of Parkinson's disease patients.
Journal
NPJ Parkinson's disease
ISSN: 2373-8057
Titre abrégé: NPJ Parkinsons Dis
Pays: United States
ID NLM: 101675390
Informations de publication
Date de publication:
02 Jan 2024
02 Jan 2024
Historique:
received:
07
02
2023
accepted:
24
11
2023
medline:
4
1
2024
pubmed:
4
1
2024
entrez:
3
1
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38167511
doi: 10.1038/s41531-023-00607-9
pii: 10.1038/s41531-023-00607-9
doi:
Types de publication
Journal Article
Langues
eng
Pagination
2Informations de copyright
© 2024. The Author(s).
Références
Muñoz-Lasso, D. C., Romá-Mateo, C., Pallardó, F. V. & Gonzalez-Cabo, P. Much more than a scaffold: cytoskeletal proteins in neurological disorders. Cells 9, 358 (2020).
pubmed: 32033020
pmcid: 7072452
doi: 10.3390/cells9020358
Rolls, M. M., Thyagarajan, P. & Feng, C. Microtubule dynamics in healthy and injured neurons. Dev. Neurobiol. 81, 321–332 (2021).
pubmed: 32291942
doi: 10.1002/dneu.22746
Waites, C., Qu, X. & Bartolini, F. The synaptic life of microtubules. Curr. Opin. Neurobiol. 69, 113–123 (2021).
pubmed: 33873059
pmcid: 8387337
doi: 10.1016/j.conb.2021.03.004
Kapitein, L. C. & Hoogenraad, C. C. Building the neuronal microtubule cytoskeleton. Neuron 87, 492–506 (2015).
pubmed: 26247859
doi: 10.1016/j.neuron.2015.05.046
Sferra, A., Nicita, F. & Bertini, E. Microtubule dysfunction: a common feature of neurodegenerative diseases. Int J. Mol. Sci. 21, 7354 (2020).
pubmed: 33027950
pmcid: 7582320
doi: 10.3390/ijms21197354
Cappelletti, G. & Cartelli, D. Acetylation of tubulin: A feasible protective target from neurodevelopment to neurodegeneration. in Neuroprotection in Autism, Schizophrenia and Alzheimer’s Disease 273–294 (Elsevier, 2020).
Cappelletti, G. et al. Linking microtubules to Parkinson’s disease: the case of parkin. Biochem Soc. Trans. 43, 292–296 (2015).
pubmed: 25849932
doi: 10.1042/BST20150007
Matamoros, A. J. & Baas, P. W. Microtubules in health and degenerative disease of the nervous system. Brain Res. Bull. 126, 217–225 (2016).
pubmed: 27365230
pmcid: 5079814
doi: 10.1016/j.brainresbull.2016.06.016
Brandt, R. & Bakota, L. Microtubule dynamics and the neurodegenerative triad of Alzheimer’s disease: the hidden connection. J. Neurochem. 143, 409–417 (2017).
pubmed: 28267200
doi: 10.1111/jnc.14011
Fanara, P. et al. Stabilization of hyperdynamic microtubules is neuroprotective in amyotrophic lateral sclerosis. J. Biol. Chem. 282, 23465–23472 (2007).
pubmed: 17567579
doi: 10.1074/jbc.M703434200
Janke, C. & Magiera, M. M. The tubulin code and its role in controlling microtubule properties and functions. Nat. Rev. Mol. Cell Biol. 21, 307–326 (2020).
pubmed: 32107477
doi: 10.1038/s41580-020-0214-3
Gadadhar, S., Bodakuntla, S., Natarajan, K. & Janke, C. The tubulin code at a glance. J. Cell Sci. 130, 1347–1353 (2017).
pubmed: 28325758
Song, Y. & Brady, S. T. Post-translational modifications of tubulin: pathways to functional diversity of microtubules. Trends Cell Biol. 25, 125–136 (2015).
pubmed: 25468068
doi: 10.1016/j.tcb.2014.10.004
L’Hernault, S. W. & Rosenbaum, J. L. Chlamydomonas alpha-tubulin is posttranslationally modified in the flagella during flagellar assembly. J. Cell Biol. 97, 258–263 (1983).
pubmed: 6863393
doi: 10.1083/jcb.97.1.258
Creppe, C. et al. Elongator controls the migration and differentiation of cortical neurons through acetylation of α-Tubulin. Cell 136, 551–564 (2009).
pubmed: 19185337
doi: 10.1016/j.cell.2008.11.043
Nekooki-Machida, Y. & Hagiwara, H. Role of tubulin acetylation in cellular functions and diseases. Med. Mol. Morphol. 53, 191–197 (2020).
pubmed: 32632910
doi: 10.1007/s00795-020-00260-8
Janke, C. & Kneussel, M. Tubulin post-translational modifications: encoding functions on the neuronal microtubule cytoskeleton. Trends Neurosci. 33, 362–72 (2010).
pubmed: 20541813
doi: 10.1016/j.tins.2010.05.001
Portran, D., Schaedel, L., Xu, Z., Théry, M. & Nachury, M. V. Tubulin acetylation protects long-lived microtubules against mechanical ageing. Nat. Cell Biol. 19, 391–398 (2017).
pubmed: 28250419
pmcid: 5376231
doi: 10.1038/ncb3481
Xu, Z. et al. Microtubules acquire resistance from mechanical breakage through intralumenal acetylation. Science 356, 328–332 (2017).
pubmed: 28428427
pmcid: 5457157
doi: 10.1126/science.aai8764
Montagnac, G. et al. TAT1 catalyses microtubule acetylation at clathrin-coated pits. Nature 502, 567–570 (2013).
pubmed: 24097348
pmcid: 3970258
doi: 10.1038/nature12571
Geeraert, C. et al. Starvation-induced hyperacetylation of tubulin is required for the stimulation of autophagy by nutrient deprivation. J. Biol. Chem. 285, 24184–24194 (2010).
pubmed: 20484055
pmcid: 2911293
doi: 10.1074/jbc.M109.091553
Reed, N. A. et al. Microtubule acetylation promotes kinesin-1 binding and transport. Curr. Biol. 16, 2166–2172 (2006).
pubmed: 17084703
doi: 10.1016/j.cub.2006.09.014
Aguilar, A. et al. Tubulin K40 acetylation is required for contact inhibition of proliferation and cell–substrate adhesion. Mol. Biol. Cell 25, 1854–1866 (2014).
pubmed: 24743598
pmcid: 4055265
doi: 10.1091/mbc.e13-10-0609
Hunn, B. H. M., Cragg, S. J., Bolam, J. P., Spillantini, M.-G. & Wade-Martins, R. Impaired intracellular trafficking defines early Parkinson’s disease. Trends Neurosci. 38, 178–188 (2015).
pubmed: 25639775
pmcid: 4740565
doi: 10.1016/j.tins.2014.12.009
Pellegrini, L., Wetzel, A., Grannó, S., Heaton, G. & Harvey, K. Back to the tubule: microtubule dynamics in Parkinson’s disease. Cell. Mol. Life Sci. 74, 409–434 (2017).
pubmed: 27600680
doi: 10.1007/s00018-016-2351-6
Cartelli, D. & Cappelletti, G. Microtubule destabilization paves the way to Parkinson’s disease. Mol. Neurobiol. 54, 6762–6774 (2017).
pubmed: 27757833
doi: 10.1007/s12035-016-0188-5
Cartelli, D. et al. Microtubule dysfunction precedes transport impairment and mitochondria damage in MPP+-induced neurodegeneration. J. Neurochem. 115, 247–258 (2010).
pubmed: 20649848
doi: 10.1111/j.1471-4159.2010.06924.x
Kim-Han, J. S., Antenor-Dorsey, J. A. & O’Malley, K. L. The Parkinsonian mimetic, MPP+, specifically impairs mitochondrial transport in dopamine axons. J. Neurosci. 31, 7212–7221 (2011).
pubmed: 21562285
pmcid: 3140916
doi: 10.1523/JNEUROSCI.0711-11.2011
Cartelli, D. et al. Microtubule alterations occur early in experimental parkinsonism and the microtubule stabilizer epothilone D is neuroprotective. Sci. Rep. 3, 1837 (2013).
pubmed: 23670541
pmcid: 3653217
doi: 10.1038/srep01837
Esteves, A. R. & Cardoso, S. M. Differential protein expression in diverse brain areas of Parkinson’s and Alzheimer’s disease patients. Sci. Rep. 10, 13149 (2020).
pubmed: 32753661
pmcid: 7403590
doi: 10.1038/s41598-020-70174-z
Panicker, N., Ge, P., Dawson, V. L. & Dawson, T. M. The cell biology of Parkinson’s disease. J. Cell Biol. 220, e00241 (2021).
Balestrino, R. & Schapira, A. H. V. Parkinson disease. Eur. J. Neurol. 27, 27–42 (2020).
pubmed: 31631455
doi: 10.1111/ene.14108
Poewe, W. et al. Parkinson disease. Nat. Rev. Dis. Prim. 3, 17013 (2017).
pubmed: 28332488
doi: 10.1038/nrdp.2017.13
Dickson, D. W. Parkinson’s Disease and Parkinsonism: neuropathology. Cold Spring Harb. Perspect. Med. 2, a009258–a009258 (2012).
pubmed: 22908195
pmcid: 3405828
doi: 10.1101/cshperspect.a009258
Spillantini, M. G. et al. Synuclein in Lewy bodies. Nature 388, 839–840 (1997).
pubmed: 9278044
doi: 10.1038/42166
Bengoa-Vergniory, N., Roberts, R. F., Wade-Martins, R. & Alegre-Abarrategui, J. Alpha-synuclein oligomers: a new hope. Acta. Neuropathol. 134, 819–838 (2017).
pubmed: 28803412
pmcid: 5663814
doi: 10.1007/s00401-017-1755-1
Valdinocci, D., Radford, R., Siow, S., Chung, R. & Pountney, D. Potential modes of intercellular α-Synuclein transmission. Int. J. Mol. Sci. 18, 469 (2017).
pubmed: 28241427
pmcid: 5344001
doi: 10.3390/ijms18020469
Uemura, N., Uemura, M. T., Luk, K. C., Lee, V. M.-Y. & Trojanowski, J. Q. Cell-to-cell transmission of Tau and α-Synuclein. Trends Mol. Med. 26, 936–952 (2020).
pubmed: 32371172
pmcid: 7529725
doi: 10.1016/j.molmed.2020.03.012
Abounit, S. et al. Tunneling nanotubes spread fibrillar α‐synuclein by intercellular trafficking of lysosomes. EMBO J. 35, 2120–2138 (2016).
pubmed: 27550960
pmcid: 5048354
doi: 10.15252/embj.201593411
Mao, X. et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353, 139–148 (2016).
doi: 10.1126/science.aah3374
Danzer, K. M. et al. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol. Neurodegener. 7, 42 (2012).
pubmed: 22920859
pmcid: 3483256
doi: 10.1186/1750-1326-7-42
Fares, M. B., Jagannath, S. & Lashuel, H. A. Reverse engineering Lewy bodies: how far have we come and how far can we go? Nat. Rev. Neurosci. 22, 111–131 (2021).
pubmed: 33432241
doi: 10.1038/s41583-020-00416-6
Takahashi, H. & Wakabayashi, K. The cellular pathology of Parkinson’s disease. Neuropathology 21, 315–322 (2001).
pubmed: 11837539
doi: 10.1046/j.1440-1789.2001.00403.x
Wakabayashi, K. et al. The lewy body in Parkinson’s disease and related neurodegenerative disorders. Mol. Neurobiol. 47, 495–508 (2013).
pubmed: 22622968
doi: 10.1007/s12035-012-8280-y
Shahmoradian, S. H. et al. Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes. Nat. Neurosci. 22, 1099–1109 (2019).
pubmed: 31235907
doi: 10.1038/s41593-019-0423-2
Moors, T. E. et al. The subcellular arrangement of alpha-synuclein proteoforms in the Parkinson’s disease brain as revealed by multicolor STED microscopy. Acta. Neuropathol. 142, 423–448 (2021).
pubmed: 34115198
pmcid: 8357756
doi: 10.1007/s00401-021-02329-9
Seebauer, L. et al. Interaction of alpha synuclein and microtubule organization is linked to impaired neuritic integrity in Parkinson’s patient-derived neuronal cells. Int. J. Mol. Sci. 23, 1812 (2022).
pubmed: 35163733
pmcid: 8836605
doi: 10.3390/ijms23031812
Calogero, A. M., Mazzetti, S., Pezzoli, G. & Cappelletti, G. Neuronal microtubules and proteins linked to Parkinson’s disease: a relevant interaction? Biol. Chem. 400, 1099–1112 (2019).
pubmed: 31256059
doi: 10.1515/hsz-2019-0142
Cartelli, D. et al. Synuclein is a novel microtubule dynamase. Sci. Rep. 6, 33289 (2016).
pubmed: 27628239
pmcid: 5024109
doi: 10.1038/srep33289
Payton, J. E., Perrin, R. J., Clayton, D. F. & George, J. M. Protein–protein interactions of alpha-synuclein in brain homogenates and transfected cells. Mol. Brain Res. 95, 138–145 (2001).
pubmed: 11687285
doi: 10.1016/S0169-328X(01)00257-1
Alim, M. A. et al. Tubulin seeds α-Synuclein fibril formation. J. Biol. Chem. 277, 2112–2117 (2002).
pubmed: 11698390
doi: 10.1074/jbc.M102981200
Alim, M. A. et al. Demonstration of a role for α-synuclein as a functional microtubule-associated protein. J. Alzheimer’s Dis. 6, 435–442 (2004).
doi: 10.3233/JAD-2004-6412
Zhou, R. M. et al. Molecular interaction of α-synuclein with tubulin influences on the polymerization of microtubule in vitro and structure of microtubule in cells. Mol. Biol. Rep. 37, 3183–3192 (2010).
pubmed: 19826908
doi: 10.1007/s11033-009-9899-2
Amadeo, A. et al. The association between α-synuclein and α-tubulin in brain synapses. Int. J. Mol. Sci. 22, 9153 (2021).
pubmed: 34502063
pmcid: 8430732
doi: 10.3390/ijms22179153
Cartelli, D. & Cappelletti, G. α-Synuclein regulates the partitioning between tubulin dimers and microtubules at neuronal growth cone. Commun. Integr. Biol. 10, e1267076 (2017).
pmcid: 5333521
doi: 10.1080/19420889.2016.1267076
Lee, H., Zhu, X., Takeda, A., Perry, G. & Smith, M. A. Emerging evidence for the neuroprotective role of α-synuclein. Exp. Neurol. 200, 1–7 (2006).
pubmed: 16780837
doi: 10.1016/j.expneurol.2006.04.024
Mazzetti, S. et al. Phospho-HDAC6 gathers into protein aggregates in Parkinson’s dsease and a typical Parkinsonisms. Front. Neurosci. 14, 784054 (2020).
Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).
pubmed: 28099414
pmcid: 5404890
doi: 10.1038/nature21029
Dheen, T. S., Kaur, C. & Ling, E.-A. Microglial activation and its implications in the brain diseases. Curr. Med. Chem. 14, 1189–1197 (2007).
pubmed: 17504139
doi: 10.2174/092986707780597961
Braak, H., Ghebremedhin, E., Rüb, U., Bratzke, H. & Del Tredici, K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res. 318, 121–134 (2004).
pubmed: 15338272
doi: 10.1007/s00441-004-0956-9
Klingelhoefer, L. & Reichmann, H. Parkinson’s disease as a multisystem disorder. J. Neural Transm. 124, 709–713 (2017).
pubmed: 28155133
doi: 10.1007/s00702-017-1692-0
Zange, L., Noack, C., Hahn, K., Stenzel, W. & Lipp, A. Phosphorylated α-synuclein in skin nerve fibres differentiates Parkinson’s disease from multiple system atrophy. Brain 138, 2310–2321 (2015).
pubmed: 26017579
doi: 10.1093/brain/awv138
Donadio, V. et al. Skin nerve misfolded α-synuclein in pure autonomic failure and Parkinson disease. Ann. Neurol. 79, 306–316 (2016).
pubmed: 26606657
doi: 10.1002/ana.24567
Mazzetti, S. et al. α-Synuclein oligomers in skin biopsy of idiopathic and monozygotic twin patients with Parkinson’s disease. Brain 143, 920–931 (2020).
pubmed: 32025699
pmcid: 7089656
doi: 10.1093/brain/awaa008
Fujiwara, H. et al. Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 4, 160–164 (2002).
pubmed: 11813001
doi: 10.1038/ncb748
Roberts, R. F., Wade-Martins, R. & Alegre-Abarrategui, J. Direct visualization of alpha-synuclein oligomers reveals previously undetected pathology in Parkinson’s disease brain. Brain 138, 1642–1657 (2015).
pubmed: 25732184
pmcid: 4614141
doi: 10.1093/brain/awv040
Caughey, B. & Lansbury, P. T. PROTOFIBRILS, PORES, FIBRILS, AND N EURODEGENERATION: separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26, 267–298 (2003).
pubmed: 12704221
doi: 10.1146/annurev.neuro.26.010302.081142
Bigi, A., Cascella, R. & Cecchi, C. α-Synuclein oligomers and fibrils: partners in crime in synucleinopathies. Neural. Regen. Res 18, 2332–2342 (2023).
pubmed: 37282450
pmcid: 10360081
doi: 10.4103/1673-5374.371345
Kovacs, G. G. et al. An antibody with high reactivity for disease-associated α-synuclein reveals extensive brain pathology. Acta. Neuropathol. 124, 37–50 (2012).
pubmed: 22370907
doi: 10.1007/s00401-012-0964-x
Fricker, M., Runions, J. & Moore, I. QUANTITATIVE FLUORESCENCE MICROSCOPY: from art to science. Annu. Rev. Plant Biol. 57, 79–107 (2006).
pubmed: 16669756
doi: 10.1146/annurev.arplant.57.032905.105239
Zinchuk, V. & Grossenbacher-Zinchuk, O. Recent advances in quantitative colocalization analysis: focus on neuroscience. Prog. Histochem. Cytochem. 44, 125–172 (2009).
pubmed: 19822255
doi: 10.1016/j.proghi.2009.03.001
Eliceiri, K. W. et al. Biological imaging software tools. Nat. Methods 9, 697–710 (2012).
pubmed: 22743775
pmcid: 3659807
doi: 10.1038/nmeth.2084
Kuusisto, E., Parkkinen, L. & Alafuzoff, I. Morphogenesis of lewy bodies: dissimilar incorporation of α-synuclein, ubiquitin, and p62. J. Neuropathol. Exp. Neurol. 62, 1241–1253 (2003).
pubmed: 14692700
doi: 10.1093/jnen/62.12.1241
Cappelletti, G., Calogero, A. M. & Rolando, C. Microtubule acetylation: a reading key to neural physiology and degeneration. Neurosci. Lett. 755, 135900 (2021).
pubmed: 33878428
doi: 10.1016/j.neulet.2021.135900
Patel, V. P. & Chu, C. T. Decreased SIRT2 activity leads to altered microtubule dynamics in oxidatively-stressed neuronal cells: Implications for Parkinson’s disease. Exp. Neurol. 257, 170–181 (2014).
pubmed: 24792244
pmcid: 4141566
doi: 10.1016/j.expneurol.2014.04.024
Abeliovich, A. & Gitler, A. D. Defects in trafficking bridge Parkinson’s disease pathology and genetics. Nature 539, 207–216 (2016).
pubmed: 27830778
doi: 10.1038/nature20414
Ren, Y., Jiang, H., Yang, F., Nakaso, K. & Feng, J. Parkin protects dopaminergic neurons against microtubule-depolymerizing toxins by attenuating microtubule-associated protein kinase activation. J. Biol. Chem. 284, 4009–4017 (2009).
pubmed: 19074146
pmcid: 2635057
doi: 10.1074/jbc.M806245200
Ren, Y. et al. Parkin mutations reduce the complexity of neuronal processes in iPSC-derived human neurons. Stem Cells 33, 68–78 (2015).
pubmed: 25332110
doi: 10.1002/stem.1854
Cartelli, D. et al. Parkin absence accelerates microtubule aging in dopaminergic neurons. Neurobiol. Aging 61, 66–74 (2018).
pubmed: 29040870
doi: 10.1016/j.neurobiolaging.2017.09.010
Cartelli, D., Goldwurm, S., Casagrande, F., Pezzoli, G. & Cappelletti, G. Microtubule destabilization is shared by genetic and idiopathic Parkinson’s disease patient fibroblasts. PLoS One 7, e37467 (2012).
pubmed: 22666358
pmcid: 3359730
doi: 10.1371/journal.pone.0037467
Godena, V. K. et al. Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. Nat. Commun. 5, 5245 (2014).
pubmed: 25316291
doi: 10.1038/ncomms6245
Fusco, G. et al. Structural basis of membrane disruption and cellular toxicity by α-synuclein oligomers. Science (1979) 358, 1440–1443 (2017).
Basso, M. et al. Proteome analysis of human substantia nigra in Parkinson’s disease. Proteomics 4, 3943–3952 (2004).
pubmed: 15526345
doi: 10.1002/pmic.200400848
Werner, C. J. Heyny-von Haussen, R., Mall, G. & Wolf, S. Proteome analysis of human substantia nigra in Parkinson’s disease. Proteom. Sci. 6, 8 (2008).
doi: 10.1186/1477-5956-6-8
Kitsou, E. et al. Identification of proteins in human substantia nigra. Proteom. Clin. Appl 2, 776–782 (2008).
doi: 10.1002/prca.200800028
Licker, V. et al. Proteomic analysis of human substantia nigra identifies novel candidates involved in Parkinson’s disease pathogenesis. Proteomics 14, 784–794 (2014).
pubmed: 24449343
doi: 10.1002/pmic.201300342
Gai, W. P. et al. In situ and in vitro study of colocalization and segregation of α-synuclein, ubiquitin, and lipids in lewy bodies. Exp. Neurol. 166, 324–333 (2000).
pubmed: 11085897
doi: 10.1006/exnr.2000.7527
Araki, K. et al. Synchrotron FTIR micro-spectroscopy for structural analysis of Lewy bodies in the brain of Parkinson’s disease patients. Sci. Rep. 5, 17625 (2015).
pubmed: 26621077
pmcid: 4664933
doi: 10.1038/srep17625
Even, A. et al. ATAT1-enriched vesicles promote microtubule acetylation via axonal transport. Sci. Adv. 5, e0041 (2019).
Coombes, C. et al. Mechanism of microtubule lumen entry for the α-tubulin acetyltransferase enzyme αTAT1. Proc. Natl Acad. Sci. 113, E7176–E7184 (2016).
pubmed: 27803321
pmcid: 5135325
doi: 10.1073/pnas.1605397113
Hubbert, C. et al. HDAC6 is a microtubule-associated deacetylase. Nature 417, 455–458 (2002).
pubmed: 12024216
doi: 10.1038/417455a
North, B. J., Marshall, B. L., Borra, M. T., Denu, J. M. & Verdin, E. The human Sir2 Ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol. Cell 11, 437–444 (2003).
pubmed: 12620231
doi: 10.1016/S1097-2765(03)00038-8
Olanow, C. W., Perl, D. P., DeMartino, G. N. & McNaught, K. S. P. Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol. 3, 496–503 (2004).
pubmed: 15261611
doi: 10.1016/S1474-4422(04)00827-0
Pandey, U. B. et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447, 860–864 (2007).
doi: 10.1038/nature05853
Francelle, L., Outeiro, T. F. & Rappold, G. A. Inhibition of HDAC6 activity protects dopaminergic neurons from alpha-synuclein toxicity. Sci. Rep. 10, 6064 (2020).
pubmed: 32269243
pmcid: 7142125
doi: 10.1038/s41598-020-62678-5
Outeiro, T. F. et al. Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317, 516–519 (2007).
pubmed: 17588900
doi: 10.1126/science.1143780
Esteves, A. R., Gozes, I. & Cardoso, S. M. The rescue of microtubule-dependent traffic recovers mitochondrial function in Parkinson’s disease. Biochim. et. Biophys. Acta. BBA Mol. Basis Dis. 1842, 7–21 (2014).
doi: 10.1016/j.bbadis.2013.10.003
Calogero, A. M. et al. Acetylated α-Tubulin and α-Synuclein: physiological interplay and contribution to α-synuclein oligomerization. Int J. Mol. Sci. 24, 12287 (2023).
pubmed: 37569662
pmcid: 10418364
doi: 10.3390/ijms241512287
Senol, A. D. et al. Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes. PLoS Biol. 19, e3001287 (2021).
doi: 10.1371/journal.pbio.3001287
Valdinocci, D., Kovarova, J., Neuzil, J. & Pountney, D. L. Alpha-synuclein aggregates associated with mitochondria in tunnelling nanotubes. Neurotox. Res. 39, 429–443 (2021).
pubmed: 32926337
doi: 10.1007/s12640-020-00285-y
d’Ydewalle, C. et al. HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1–induced Charcot-Marie-Tooth disease. Nat. Med. 17, 968–974 (2011).
pubmed: 21785432
doi: 10.1038/nm.2396
Kim, J.-Y. et al. HDAC6 inhibitors rescued the defective axonal mitochondrial movement in motor neurons derived from the induced pluripotent stem cells of peripheral neuropathy patients with HSPB1 mutation. Stem Cells Int. 2016, 1–14 (2016).
Gal, J. et al. HDAC6 regulates mutant SOD1 aggregation through two SMIR Motifs and tubulin acetylation. J. Biol. Chem. 288, 15035–15045 (2013).
pubmed: 23580651
pmcid: 3663524
doi: 10.1074/jbc.M112.431957
Lee, J.-Y. et al. Uncoupling of protein aggregation and neurodegeneration in a mouse amyotrophic lateral sclerosis model. Neurodegener. Dis. 15, 339–349 (2015).
pubmed: 26360702
doi: 10.1159/000437208
Dompierre, J. P. et al. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation. J. Neurosci. 27, 3571–3583 (2007).
pubmed: 17392473
pmcid: 6672116
doi: 10.1523/JNEUROSCI.0037-07.2007
Tsushima, H. et al. HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity. Nat. Commun. 6, 7781 (2015).
pubmed: 26198811
doi: 10.1038/ncomms8781
Zhang, F. et al. Posttranslational modifications of α-tubulin in Alzheimer disease. Transl. Neurodegener. 4, 9 (2015).
pubmed: 26029362
pmcid: 4448339
doi: 10.1186/s40035-015-0030-4
Martínez-Hernández, J. et al. Crosstalk between acetylation and the tyrosination/detyrosination cycle of α-tubulin in Alzheimer’s disease. Front. Cell Dev. Biol. 10, 223–251 (2022).
Hughes, A. J., Daniel, S. E., Kilford, L. & Lees, A. J. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J. Neurol. Neurosurg. Psychiatr. 55, 181–184 (1992).
doi: 10.1136/jnnp.55.3.181
Hughes, A. J., Daniel, S. E. & Lees, A. J. Improved accuracy of clinical diagnosis of Lewy body Parkinson’s disease. Neurology 57, 1497–1499 (2001).
pubmed: 11673599
doi: 10.1212/WNL.57.8.1497
Alafuzoff, I. et al. Staging/typing of lewy body related α-synuclein pathology: a study of the BrainNet Europe consortium. Acta. Neuropathol. 117, 635–652 (2009).
pubmed: 19330340
doi: 10.1007/s00401-009-0523-2
Hoehn, M. M. & Yahr, M. D. Parkinsonism: onset, progression, and mortality. Neurology 17, 427–427 (1967).
pubmed: 6067254
doi: 10.1212/WNL.17.5.427
Filocamo, M. et al. Telethon network of genetic biobanks: a key service for diagnosis and research on rare diseases. Orphanet. J. Rare Dis. 8, 129 (2013).
pubmed: 24004821
pmcid: 3766640
doi: 10.1186/1750-1172-8-129
Piperno, G. & Fuller, M. T. Monoclonal antibodies specific for an acetylated form of alpha-tubulin recognize the antigen in cilia and flagella from a variety of organisms. J. Cell Biol. 101, 2085–2094 (1985).
pubmed: 2415535
doi: 10.1083/jcb.101.6.2085
Castoldi, M. & Popov, A. V. Purification of brain tubulin through two cycles of polymerization–depolymerization in a high-molarity buffer. Protein Expr. Purif. 32, 83–88 (2003).
pubmed: 14680943
doi: 10.1016/S1046-5928(03)00218-3
Bolte, S. & Cordelières, F. P. A guided tour into subcellular colocalization analysis in light microscopy. J. Microsci. 224, 213–232 (2006).
doi: 10.1111/j.1365-2818.2006.01706.x