Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter July 19, 2019

Neuronal microtubules and proteins linked to Parkinson’s disease: a relevant interaction?

  • Alessandra M. Calogero EMAIL logo , Samanta Mazzetti , Gianni Pezzoli and Graziella Cappelletti ORCID logo EMAIL logo
From the journal Biological Chemistry


Neuronal microtubules are key determinants of cell morphology, differentiation, migration and polarity, and contribute to intracellular trafficking along axons and dendrites. Microtubules are strictly regulated and alterations in their dynamics can lead to catastrophic effects in the neuron. Indeed, the importance of the microtubule cytoskeleton in many human diseases is emerging. Remarkably, a growing body of evidence indicates that microtubule defects could be linked to Parkinson’s disease pathogenesis. Only a few of the causes of the progressive neuronal loss underlying this disorder have been identified. They include gene mutations and toxin exposure, but the trigger leading to neurodegeneration is still unknown. In this scenario, the evidence showing that mutated proteins in Parkinson’s disease are involved in the regulation of the microtubule cytoskeleton is intriguing. Here, we focus on α-Synuclein, Parkin and Leucine-rich repeat kinase 2 (LRRK2), the three main proteins linked to the familial forms of the disease. The aim is to dissect their interaction with tubulin and microtubules in both physiological and pathological conditions, in which these proteins are overexpressed, mutated or absent. We highlight the relevance of such an interaction and suggest that these proteins could trigger neurodegeneration via defective regulation of the microtubule cytoskeleton.


The authors are grateful to Fondazione Grigioni per il Morbo di Parkinson, Milan, Italy, for the long-standing support to A.M.C, S.M., and G.C., and to BTN (Nervous Tissue Bank, Milan, sponsored by Fondazione Grigioni per il Morbo di Parkinson) for supplying human tissues. The authors thank Dr. Jennifer S. Hartwig and Dr. Milo J. Basellini for reading and editing the manuscript. The authors are also grateful to all the present and former group members for their contributions and apologize for each possible involuntary paper omission.


Alim, M.A., Hossain, M.S., Arima, K., Takeda, K., Izumiyama, Y., Nakamura, M., Kaji, H., Shinoda, T., Hisanaga, S., and Uéda, K. (2002). Tubulin seeds α-synuclein fibril formation. J. Biol. Chem. 277, 2112–2117.10.1074/jbc.M102981200Search in Google Scholar PubMed

Alim, M.A., Ma, Q.L., Takeda, K., Aizawa, T., Matsubara, M., Nakamura, M., Asada, A., Saito, T., Kaji, H., Yoshii, M., et al. (2004). Demonstration of a role for α-synuclein as a functional microtubule-associated protein. J. Alzheimers Dis. 6, 435–442.10.3233/JAD-2004-6412Search in Google Scholar PubMed

Alves da Costa, C., Duplan, E., Rouland, L., and Checler, F. (2019). The transcription factor function of parkin: breaking the dogma. Front Neurosci. 12, 965.10.3389/fnins.2018.00965Search in Google Scholar PubMed PubMed Central

Appel-Cresswell, S., Vilarino-Guell, C., Encarnacion, M., Sherman, H., Yu, I., Shah, B., Weir, D., Thompson, C., Szu-Tu, C., Trinh, J., et al. (2013). Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson’s disease. Mov. Disord. 28, 811–813.10.1002/mds.25421Search in Google Scholar PubMed

Auluck, P.K., Caraveo, G., and Lindquist, S. (2010). α-Synuclein: membrane interactions and toxicity in Parkinson’s disease. Annu. Rev. Cell Dev. Biol. 26, 211–233.10.1146/annurev.cellbio.042308.113313Search in Google Scholar PubMed

Baas, P.W., Rao, A.N., Matamoros, A.J., and Leo, L. (2016). Stability properties of neuronal microtubules. Cytoskeleton 73, 442–460.10.1002/cm.21286Search in Google Scholar PubMed PubMed Central

Bartels, T., Choi, J.G., and Selkoe, D.J. (2011). α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477, 107–110.10.1038/nature10324Search in Google Scholar PubMed PubMed Central

Beach, T.G., Adler, C.H., Sue, L.I., Vedders, L., Lue, L.F., White, C.L., Akiyama, H., Caviness, J.N., Shill, H.A., Sabbagh, M.N., et al. (2010). Multi-organ distribution of phosphorylated α-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol. 119, 689–702.10.1007/s00401-010-0664-3Search in Google Scholar PubMed PubMed Central

Benskey, M.J., Perez, R.G., and Manfredsson, F.P. (2016). The contribution of alpha synuclein to neuronal survival and function – implications for Parkinson’s disease. J. Neurochem. 137, 331–359.10.1111/jnc.13570Search in Google Scholar PubMed PubMed Central

Borgs, L., Peyre, E., Alix, P., Hanon, K., Grobarczyk, B., Godin, J.D., Purnelle, A., Krusy, N., Maquet, P., Lefebvre, P., et al. (2016). Dopaminergic neurons differentiating from LRRK2 G2019S induced pluripotent stem cells show early neuritic branching defects. Sci. Rep. 6, 33377.10.1038/srep33377Search in Google Scholar PubMed PubMed Central

Braak, H., De Vos, R.A., Bohl, J., and Del Tredici, K. (2006). Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci. Lett. 396, 67–72.10.1016/j.neulet.2005.11.012Search in Google Scholar PubMed

Brunden, K.R., Lee, V.M.-Y., Smith III, A.B., Trojanowski, J.Q., and Ballatore, C. (2017). Altered microtubule dynamics in neurodegenerative disease: therapeutic potential of microtubule-stabilizing drugs. Neurobiol. Dis. 105, 328–335.10.1016/j.nbd.2016.12.021Search in Google Scholar PubMed PubMed Central

Brundin, P. and Melki, R. (2017). Prying into the prion hypothesis for Parkinson’s disease. J. Neurosci. 37, 9808–9818.10.1523/JNEUROSCI.1788-16.2017Search in Google Scholar PubMed PubMed Central

Burré, J., Sharma, M., Tsetsenis, T., Buchman, V., Etherton, M.R., and Südhof, T.C. (2010). Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329, 1663–1667.10.1126/science.1195227Search in Google Scholar PubMed PubMed Central

Cappelletti, G., Surrey, T., and Maci, R. (2005). The Parkinsonism producing neurotoxin MPP+ affects microtubule dynamics by acting as a destabilising factor. FEBS Lett. 579, 4781–4786.10.1016/j.febslet.2005.07.058Search in Google Scholar PubMed

Cappelletti, G., Cartelli, D., Passarella, D., and Christodoulou, M.S. (2017). Microtubule-directed therapeutic strategy for neurodegenerative disorders: starting from the basis and looking on the emergences. Curr. Pharm. Des. 23, 784–808.10.2174/1381612822666161214150544Search in Google Scholar PubMed

Carnwath, T., Mohammed, R., and Tsiang, D. (2018). The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson’s disease. Neuropsychiatr. Dis. Treat. 14, 1685–1695.10.2147/NDT.S166322Search in Google Scholar PubMed PubMed Central

Cartelli, D. and Cappelletti, G. (2017a). Microtubule destabilization paves the way to Parkinson’s disease. Mol. Neurobiol. 54, 6762–6774.10.1007/s12035-016-0188-5Search in Google Scholar PubMed

Cartelli, D. and Cappelletti, G. (2017b). α-Synuclein regulates the partitioning between tubulin dimers and microtubules at neuronal growth cone. Commun. Integr. Biol. 10, e1267076.10.1080/19420889.2016.1267076Search in Google Scholar

Cartelli, D., Ronchi, C., Maggioni, M.G., Rodighiero, S., Giavini, E., and Cappelletti, G. (2010). Microtubule dysfunction precedes transport impairment and mitochondria damage in MPP+-induced neurodegeneration. J. Neurochem. 115, 247–258.10.1111/j.1471-4159.2010.06924.xSearch in Google Scholar PubMed

Cartelli, D., Goldwurm, S., Casagrande, F., Pezzoli, G., and Cappelletti, G. (2012). Microtubule destabilization is shared by genetic and idiopathic Parkinson’s disease patient fibroblasts. PLoS One 7, e37467.10.1371/journal.pone.0037467Search in Google Scholar

Cartelli, D., Casagrande, F., Busceti, C.L., Bucci, D., Molinaro, G., Traficante, A., Passarella, D., Giavini, E., Pezzoli, G., Battaglia, G., et al. (2013). Microtubule alterations occur early in experimental Parkinsonism and the microtubule stabilizer epothilone D is neuroprotective. Sci. Rep. 3, 1837.10.1038/srep01837Search in Google Scholar

Cartelli, D., Aliverti, A., Barbiroli, A., Santambrogio, C., Ragg, E.M., Casagrande, F.V., Cantele, F., Beltramone, S., Marangon, J., De Gregorio, C., et al. (2016). α-Synuclein is a novel microtubule dynamase. Sci. Rep. 6, 33289.10.1038/srep33289Search in Google Scholar

Cartelli, D., Amadeo, A., Calogero, A.M., Casagrande, F.V.M., De Gregorio, C., Gioria, M., Kuzumaki, N., Costa, I., Sassone, J., Ciammola, A., et al. (2018). Parkin absence accelerates microtubule aging in dopaminergic neurons. Neurobiol. Aging 61, 66–74.10.1016/j.neurobiolaging.2017.09.010Search in Google Scholar

Casarejos, M.J., Menéndez, J., Solano, R.M., Rodríguez-Navarro, J.A., García De Yébenes, J., and Mena, M.A. (2006). Susceptibility to rotenone is increased in neurons from Parkin null mice and is reduced by minocycline. J. Neurochem. 97, 934–946.10.1111/j.1471-4159.2006.03777.xSearch in Google Scholar

Chan, S.L., Chua, L.-L., Angeles, D.C., and Tan, E.-K. (2014). MAP1B rescues LRRK2 mutant-mediated cytotoxicity. Mol. Brain 7, 1–4.10.1186/1756-6606-7-29Search in Google Scholar

Chartier-Harlin, M.C., Kachergus, J., Roumier, C., Mouroux, V., Douay, X., Lincoln, S., Levecque, C., Larvor, L., Andrieux, J., Hulihan, M., et al. (2004). Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364, 1167–1169.10.1016/S0140-6736(04)17103-1Search in Google Scholar

Chen, L., Jin, J., Davis, J., Zhou, Y., Wang, Y., Liu, J., Lockhart, P.J., and Zhang, J. (2007). Oligomeric alpha-synuclein inhibits tubulin polymerization. Biochem. Biophys. Res. Commun. 356,548–553.10.1016/j.bbrc.2007.02.163Search in Google Scholar PubMed

Civiero, L., Cogo, S., Biosa, A., and Greggio, E. (2018). The role of LRRK2 in cytoskeletal dynamics. Biochem. Soc. Trans. 46, 1653–1663.10.1042/BST20180469Search in Google Scholar PubMed

Cookson, M.R. (2015). LRRK2 pathways leading to neurodegeneration. Curr. Neurol. Neurosci. Rep. 15, 42.10.1007/s11910-015-0564-ySearch in Google Scholar PubMed PubMed Central

Cookson, M.R., Lockhart, P.J., McLendon, C., O’Farrell, C., Schlossmacher, M., and Farrer, M.J. (2003). RING finger 1 mutations in Parkin produce altered localization of the protein. Hum. Mol. Genet. 12, 2957–2965.10.1093/hmg/ddg328Search in Google Scholar PubMed

Corti, O., Lesage, S., and Brice, A. (2011). What genetics tells us about the causes and mechanisms of Parkinson’s disease. Physiol. Rev. 91, 1161–1218.10.1152/physrev.00022.2010Search in Google Scholar PubMed

Dawson, T.M. and Dawson, V.L. (2014). Parkin plays a role in sporadic Parkinson’s disease. Neurodegener. Dis. 13, 69–71.10.1159/000354307Search in Google Scholar PubMed PubMed Central

Eguchi, K., Taoufiq, Z., Thorn-Seshold, O., Trauner, D., Hasegawa, M., and Takahashi, T. (2017). Wild-Type monomeric α-Synuclein can impair vesicle endocytosis and synaptic fidelity via tubulin polymerization at the Calyx of Held. J. Neurosci. 37, 6043–6052.10.1523/JNEUROSCI.0179-17.2017Search in Google Scholar PubMed PubMed Central

Esteves, A.R., Swerdlow, R.H., and Cardoso, S.M. (2014). LRRK2, a puzzling protein: insights into Parkinson’s disease pathogenesis. Exp. Neurol. 261, 206–216.10.1016/j.expneurol.2014.05.025Search in Google Scholar PubMed PubMed Central

Esteves, A.R., Palma, A.M., Gomes, R., Santos, D., Silva, D.F., and Cardoso, S.M. (2018). Acetylation as a major determinant to microtubule-dependent autophagy: relevance to Alzheimer’s and Parkinson disease pathology. Biochim. Biophys. Acta Mol. Basis Dis. S09254439, 30475–30477.10.1016/j.bbadis.2018.11.014Search in Google Scholar PubMed

Farrer, M., Kachergus, J., Forno, L., Lincoln, S., Wang, D.S., Hulihan, M., Maraganore, D., Gwinn-Hardy, K., Wszolek, Z., Dickson, D., et al. (2004). Comparison of kindreds with Parkinsonism and α-synuclein genomic multiplications. Ann. Neurol. 55, 174–179.10.1002/ana.10846Search in Google Scholar PubMed

Feng, J. (2006). Microtubule: a common target for Parkin and Parkinson’s disease toxins. Neuroscientist 12, 469–476.10.1177/1073858406293853Search in Google Scholar PubMed

Gandhi, P.N., Wang, X., Zhu, X., Chen, S.G., and Wilson-Delfosse, A.L. (2008). The Roc domain of leucine-rich repeat kinase 2 is sufficient for interaction with microtubules. J. Neurosci. Res. 86, 1711–1720.10.1002/jnr.21622Search in Google Scholar PubMed PubMed Central

George, J.M. (2002). The synucleins. Genome Biol. 3, reviews3002.10.1186/gb-2001-3-1-reviews3002Search in Google Scholar

Gillardon, F. (2009). Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability – a point of convergence in Parkinsonian neurodegeneration? J. Neurochem. 110, 1514–1522.10.1111/j.1471-4159.2009.06235.xSearch in Google Scholar PubMed

Gladkova, C., Maslen, S.L., Skehel, J.M., and Komander, D. (2018). Mechanism of parkin activation by PINK1. Nature 559, 410–414.10.1038/s41586-018-0224-xSearch in Google Scholar PubMed PubMed Central

Gloeckner, C.J., Kinkl, N., Schumacher, A., Braun, R.J., O’Neill, E., Meitinger, T., Kolch, W., Prokisch, H., and Ueffing, M. (2006). The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum. Mol. Genet. 15, 223–232.10.1093/hmg/ddi439Search in Google Scholar PubMed

Godena, V.K., Brookes-Hocking, N., Moller, A., Shaw, G., Oswald, M., Sancho, R.M., Miller, C.C., Whitworth, A.J., and De Vos, K.J. (2014). Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. Nat. Commun. 5, 5245.10.1038/ncomms6245Search in Google Scholar PubMed PubMed Central

Goedert, M., Jakes, R., and Spillantini, M.G. (2017). The synucleinopathies: twenty years on. J. Parkinsons. Dis. 7, S51–S69.10.3233/JPD-179005Search in Google Scholar PubMed PubMed Central

Goodson, H.V. and Jonasson, E.M. (2018). Microtubules and microtubule-associated proteins. Cold Spring Harb. Perspect. Biol. 10, a022608.10.1101/cshperspect.a022608Search in Google Scholar PubMed PubMed Central

Gu, W.J., Corti, O., Araujo, F., Hampe, C., Jacquier, S., Lücking, C.B., Abbas, N., Duyckaerts, C., Rooney, T., Pradier, L., et al. (2003). The C289G and C418R missense mutations cause rapid sequestration of human Parkin into insoluble aggregates. Neurobiol. Dis. 14, 357–364.10.1016/j.nbd.2003.08.011Search in Google Scholar PubMed

Hampe, C., Ardila-Osorio, H., Fournier, M., Brice, A., and Corti, O. (2006). Biochemical analysis of Parkinson’s disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity. Hum. Mol. Genet. 15, 2059–2075.10.1093/hmg/ddl131Search in Google Scholar PubMed

Harvey, K. and Outeiro, T.F. (2019). The role of LRRK2 in cell signalling. Biochem. Soc. Trans. 47, 197–207.10.1042/BST20180464Search in Google Scholar PubMed

Hoffman-Zacharska, D., Koziorowski, D., Ross, O.A., Milewski, M., Poznański, J., Jurek, M., Wszolek, Z.K., Soto-Ortolaza, A., Awek, J.A.S, Janik, P., et al. (2013). Novel A18T and pA29S substitutions in α-synuclein may be associated with sporadic Parkinson’s disease. Parkinsonism Relat. Disord. 19, 1057–1060.10.1016/j.parkreldis.2013.07.011Search in Google Scholar PubMed PubMed Central

Hoogenraad, C.C. and Bradke, F. (2009). Control of neuronal polarity and plasticity – a renaissance for microtubules? Trends Cell Biol. 19, 669–676.10.1016/j.tcb.2009.08.006Search in Google Scholar PubMed

Huang, M., Wang, B., Li, X., Fu, C., Wang, C., and Kang, X. (2019). α-Synuclein: a multifunctional player in exocytosis, endocytosis, and vesicle recycling. Front Neurosci. 13, 28.10.3389/fnins.2019.00028Search in Google Scholar

Ibáñez, P., Bonnet, A.M., Débarges, B., Lohmann, E., Tison, F., Pollak, P., Agid, Y., Dürr, A., and Brice, A. (2004). Causal relation between α-synuclein gene duplication and familial Parkinson’s disease. Lancet 364, 1169–1171.10.1016/S0140-6736(04)17104-3Search in Google Scholar

Imai, Y., Soda, M., and Takahashi, R. (2000). Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J. Biol. Chem. 275, 35661–35664.10.1074/jbc.C000447200Search in Google Scholar

Iwai, A., Masliah, E., Yoshimoto, M., Ge, N., Flanagan, L., de Silva, H.A., Kittel, A., and Saitoh, T. (1995). The precursor protein of non-Aβ component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 14, 467–475.10.1016/0896-6273(95)90302-XSearch in Google Scholar

Jakes, R., Spillantini, M.G., and Goedert, M. (1994). Identification of two distinct synucleins from human brain. FEBS Lett. 345, 27–32.10.1016/0014-5793(94)00395-5Search in Google Scholar

Jiang, H., Ren, Y., Yuen, E.Y., Zhong, P., Ghaedi, M., Hu, Z., Azabdaftari, G., Nakaso, K., Yan, Z., and Feng, J. (2012). Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nat. Commun. 3, 668.10.1038/ncomms1669Search in Google Scholar PubMed PubMed Central

Kabuta, T., Setsuie, R., Mitsui, T., Kinugawa, A., Sakurai, M., Aoki, S., Uchida, K., and Wada, K. (2008). Aberrant molecular properties shared by familial Parkinson’s disease-associated mutant UCH-L1 and carbonyl-modified UCH-L1. Hum. Mol. Genet. 17, 1482–1496.10.1093/hmg/ddn037Search in Google Scholar PubMed

Kapitein, L.C. and Hoogenraad, C.C. (2015). Building the neuronal microtubule cytoskeleton. Neuron 87, 492–506.10.1016/j.neuron.2015.05.046Search in Google Scholar PubMed

Kawakami, F., Yabata, T., Ohta, E., Maekawa, T., Shimada, N., Suzuki, M., Maruyama, H., Ichikawa, T., and Obata, F. (2012). LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth. PLoS One 7, e30834.10.1371/journal.pone.0030834Search in Google Scholar PubMed PubMed Central

Kelliher, M.T., Saunders, H.A., and Wildonger, J. (2019). Microtubule control of functional architecture in neurons. Curr. Opin. Neurobiol. 6, 39–45.10.1016/j.conb.2019.01.003Search in Google Scholar PubMed PubMed Central

Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., Yokochi, M., Mizuno, Y., and Shimizu, N. (1998). Mutations in the parkin gene cause autosomal recessive juvenile Parkinsonism. Nature 392, 605–608.10.1038/33416Search in Google Scholar PubMed

Kluss, J.H., Mamais, A., and Cookson, M.R. (2019). LRRK2 links genetic and sporadic Parkinson’s disease. Biochem. Soc. Trans. 47, 651–661.10.1042/BST20180462Search in Google Scholar PubMed PubMed Central

Kruger, R., Kuhn, W., Muller, T., Woitalla, D., Graeber, M., Kosel, S., Przuntek, H., Epplen, J.T., Schols, L., and Riess, O. (1998). Ala30Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nat. Genet. 18, 106–108.10.1038/ng0298-106Search in Google Scholar PubMed

Lassen, L.B., Reimer, L., Ferreira, N., Betzer, C., and Jensen, P.H. (2016). Protein partners of α-synuclein in health and disease. Brain Pathol. 26, 389–397.10.1111/bpa.12374Search in Google Scholar PubMed PubMed Central

Law, B.M., Spain, V.A., Leinster, V.H., Chia, R., Beilina, A., Cho, H.J., Taymans, J.M., Urban, M.K., Sancho, R.M., Blanca Ramírez, M., et al. (2014). A direct interaction between leucine-rich repeat kinase 2 and specific β-tubulin isoforms regulates tubulin. J. Biol. Chem. 289, 895–908.10.1074/jbc.M113.507913Search in Google Scholar PubMed PubMed Central

Lee, H.G., Zhu, X., Takeda, A., Perry, G., and Smith, M.A. (2006). Emerging evidence for the neuroprotective role of α-synuclein. Exp. Neurol. 200, 1–7.10.1016/j.expneurol.2006.04.024Search in Google Scholar PubMed

Lee, S., Liu, H.-P., Lin, W.-Y., Guo, H., and Lu, B. (2010). LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction. J. Neurosci. 30, 16959–16969.10.1523/JNEUROSCI.1807-10.2010Search in Google Scholar PubMed PubMed Central

Lesage, S., Anheim, M., Letournel, F., Bousset, L., Honoré, A., Rozas, N., Pieri, L., Madiona, K., Dürr, A., Melki, R., et al. (2013). G51D α-synuclein mutation causes a novel Parkinsonian-pyramidal syndrome. Ann. Neurol. 73, 459–471.10.1002/ana.23894Search in Google Scholar PubMed

Li, J.Q., Tan, L., and Yu, J.T. (2014). The role of the LRRK2 gene in Parkinsonism. Mol. Neurodegener. 9, 47.10.1186/1750-1326-9-47Search in Google Scholar PubMed PubMed Central

Longhena, F., Faustini, G., Spillantini, M.G., and Bellucci, A. (2019). Living in promiscuity: the multiple partners of α-synuclein at the synapse in physiology and pathology. Int. J. Mol. Sci. 20, 1–24.10.3390/ijms20010141Search in Google Scholar PubMed PubMed Central

Maroteaux, L., Campanelli, J., and Scheller, R.H. (1988). Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J. Neurosci. 8, 2804–2815.10.1523/JNEUROSCI.08-08-02804.1988Search in Google Scholar

Mehra, S., Sahay, S., and Maji, S.K. (2019). α-Synuclein misfolding and aggregation: implications in Parkinson’s disease pathogenesis. Biochim. Biophys. Acta Proteins Proteomics. in Google Scholar

Miklossy, J., Arai, T., Guo, J.P., Klegeris, A., Yu, S., McGeer, E.G., and McGeer, P.L. (2006). LRRK2 expression in normal and pathologic human brain and in human cell lines. J. Neuropathol. Exp. Neurol. 65, 953–963.10.1097/01.jnen.0000235121.98052.54Search in Google Scholar

Nakayama, K., Suzuki, Y., and Yazawa, I. (2012). Binding of neuronal α-synuclein to β-III tubulin and accumulation in a model of multiple system atrophy. Biochem. Biophys. Res. Commun. 417, 1170–1175.10.1016/j.bbrc.2011.12.092Search in Google Scholar

Nalls, M.A., Plagnol, V., Hernandez, D.G., Sharma, M., Sheerin, U.M., Saad, M., Simón-Sánchez, J., Schulte, C., Lesage, S., Sveinbjörnsdóttir, S., et al. (2011). Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet 377, 641–649.10.1016/S0140-6736(10)62345-8Search in Google Scholar

Obergasteiger, J., Frapporti, G., Pramstaller, P.P., Hicks, A.A., and Volta, M. (2018). A new hypothesis for Parkinson’s disease pathogenesis: GTPase-p38 MAPK signaling and autophagy as convergence points of etiology and genomics. Mol. Neurodegener. 13, 1–17.10.1186/s13024-018-0273-5Search in Google Scholar PubMed PubMed Central

Outeiro, T.F., Kontopoulos, E., Altmann, S.M., Kufareva, I., Strathearn, K.E., Amore, A.M., Volk, C.B., Maxwell, M.M., Rochet, J.C., McLean, P.J., et al. (2007). Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317, 516–551.10.1126/science.1143780Search in Google Scholar PubMed

Outeiro, T.F., Harvey, K., Dominguez-Meijide, A., and Gerhardt, E. (2019). LRRK2, α-synuclein, and tau: partners in crime or unfortunate bystanders? Biochem. Soc. Trans. 47, 827–838.10.1042/BST20180466Search in Google Scholar PubMed

Paisán-Ruíz, C., Jain, S., Evans, E.W., Gilks, W.P., Simón, J., van der Brug, M., López de Munain, A., Aparicio, S., Gil, A.M., Khan, N., et al. (2004). Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44, 595–600.10.1016/j.neuron.2004.10.023Search in Google Scholar PubMed

Park, J.H. and Roll-Mecak, A. (2018). The tubulin code in neuronal polarity. Curr. Opin. Neurobiol. 51, 95–102.10.1016/j.conb.2018.03.001Search in Google Scholar PubMed PubMed Central

Pasanen, P., Myllykangas, L., Siitonen, M., Raunio, A., Kaakkola, S., Lyytinen, J., Tienari, P.J., Pöyhönen, M., and Paetau, A. (2014). A novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson’s disease-type pathology. Neurobiol. Aging 35, 2180.e1–e2180.e5.10.1016/j.neurobiolaging.2014.03.024Search in Google Scholar

Payton, J.E., Perrin, R.J., Clayton, D.F., and George, J.M. (2001). Protein-protein interactions of alpha-synuclein in brain homogenates and transfected cells. Mol. Brain Res. 95, 138–145.10.1016/S0169-328X(01)00257-1Search in Google Scholar

Pellegrini, L., Wetzel, A., Grannò, S., Heaton, G., and Harvey, K. (2017). Back to the tubule: microtubule dynamics in Parkinson’s disease. Cell. Mol. Life Sci. 74, 409–434.10.1007/s00018-016-2351-6Search in Google Scholar PubMed PubMed Central

Penazzi, L., Bakota, L., and Brandt, R. (2016). Microtubule dynamics in neuronal development, plasticity, and neurodegeneration. Int. Rev. Cell Mol. Biol. 321, 89–169.10.1016/bs.ircmb.2015.09.004Search in Google Scholar PubMed

Pfeffer, S.R. (2018). LRRK2 and Rab GTPases. Biochem. Soc. Trans. 46, 1707–1712.10.1042/BST20180470Search in Google Scholar PubMed

Pickrell, A.M. and Youle, R.J. (2015). The roles of PINK1, Parkin and mitochondrial fidelity in PD. 85, 257–273.10.1016/j.neuron.2014.12.007Search in Google Scholar

Polymeropoulos, M.H., Lavedan, C., Leroy, E., Ide, S.E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., et al. (1997). Mutation in the α-Synuclein gene identified in families with Parkinson’s disease. Science 276, 2045–2047.10.1126/science.276.5321.2045Search in Google Scholar PubMed

Portran, D., Schaedel, L., Xu, Z., Théry, M., and Nachury, M.V. (2017). Tubulin acetylation protects long-lived microtubules against mechanical ageing. Nat. Cell Biol. 19, 391–398.10.1038/ncb3481Search in Google Scholar PubMed PubMed Central

Purlyte, E., Dhekne, H.S., Sarhan, A.R., Gomez, R., Lis, P., Wightman, M., Martinez, T.N., Tonelli, F., Pfeffer, S.R., and Alessi, D.R. (2018). Rab29 activation of the Parkinson’s disease-associated LRRK2 kinase. EMBO J. 37, 1–18.10.15252/embj.201798099Search in Google Scholar PubMed PubMed Central

Qing, H., Wong, W., McGeer, E.G., and McGeer, P.L. (2009). Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications. Biochem. Biophys. Res. Commun. 387, 149–152.10.1016/j.bbrc.2009.06.142Search in Google Scholar PubMed

Ramonet, D., Daher, J.P., Lin, B.M., Stafa, K., Kim, J., Banerjee, R., Westerlund, M., Pletnikova, O., Glauser, L., Yang, L., et al. (2011). Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS One 6, e18568.10.1371/journal.pone.0018568Search in Google Scholar PubMed PubMed Central

Ren, Y., Zhao, J., and Feng, J. (2003). Parkin binds to α/β tubulin and increases their ubiquitination and degradation. J. Neurosci. 23, 3316–3324.10.1523/JNEUROSCI.23-08-03316.2003Search in Google Scholar

Ren, Y., Jiang, H., Yang, F., Nakaso, K., and Feng, J. (2009). Parkin protects dopaminergic neurons against microtubule-depolymerizing toxins by attenuating microtubule-associated protein kinase activation. J. Biol. Chem. 284, 4009–4017.10.1074/jbc.M806245200Search in Google Scholar PubMed PubMed Central

Ren, Y., Jiang, H., Hu, Z., Fan, K., Wang, J., Janoschka, S., Wang, X., Ge, S., and Feng, J. (2015). Parkin mutations reduce the complexity of neuronal processes in iPSC-derived human neurons. Stem Cells 33, 68–78.10.1002/stem.1854Search in Google Scholar PubMed PubMed Central

Rideout, H.J. and Stefanis, L. (2014). The neurobiology of LRRK2 and its role in the pathogenesis of Parkinson’s disease. Neurochem. Res. 39, 576–592.10.1007/s11064-013-1073-5Search in Google Scholar PubMed

Riley, B.E., Lougheed, J.C., Callaway, K., Velasquez, M., Brecht, E., Nguyen, L., Shaler, T., Walker, D., Yang, Y., Regnstrom, K., et al. (2013). Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases. Nat. Commun. 4, 1982.10.1038/ncomms2982Search in Google Scholar PubMed PubMed Central

Rocha, E.M., De Miranda, B., and Sanders, L.H. (2018). Alpha-synuclein: pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease. Neurobiol. Dis. 109, 249–257.10.1016/j.nbd.2017.04.004Search in Google Scholar PubMed

Sancho, R.M., Law, B.M., and Harvey, K. (2009). Mutations in the LRRK2 Roc-COR tandem domain link Parkinson’s disease to Wnt signalling pathways. Hum. Mol. Genet. 18, 3955–3968.10.1093/hmg/ddp337Search in Google Scholar PubMed PubMed Central

Sassone, J., Serratto, G., Valtorta, F., Silani, V., Passafaro, M., and Ciammola, A. (2017). The synaptic function of parkin. Brain 140, 2265–2272.10.1093/brain/awx006Search in Google Scholar PubMed

Sheng, C., Heng, X., Zhang, G., Xiong, R., Li, H., Zhang, S., and Chen, S. (2013). DJ-1 deficiency perturbs microtubule dynamics and impairs striatal neurite outgrowth. Neurobiol. Aging 34, 489–498.10.1016/j.neurobiolaging.2012.04.008Search in Google Scholar PubMed

Shimura, H., Hattori, N., Kubo, S.I., Mizuno, Y., Asakawa, S., Minoshima, S., Shimizu, N., Iwai, K., Chiba, T., Tanaka, K., et al. (2000). Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat. Genet. 25, 302–305.10.1038/77060Search in Google Scholar PubMed

Singleton, A.B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., Hulihan, M., Peuralinna, T., Dutra, A., Nussbaum, R., et al. (2003). Alpha-synuclein locus triplication causes Parkinson’s disease. Science 302, 841.10.1126/science.1090278Search in Google Scholar PubMed

Song, Y. and Brady, S.T. (2015). Post-translational modifications of tubulin: pathways to functional diversity of microtubules. Trends Cell Biol. 25, 125–136.10.1016/j.tcb.2014.10.004Search in Google Scholar PubMed PubMed Central

Spillantini, M.G. and Goedert, M. (2018). Neurodegeneration and the ordered assembly of α-synuclein. Cell Tissue Res. 373, 137–148.10.1007/s00441-017-2706-9Search in Google Scholar PubMed PubMed Central

Spillantini, M.G., Schmidt, M.L., Lee, V.M.Y., Trojanowski, J.Q., Jakes, R., and Goedert, M. (1997). α-Synuclein in Lewy bodies. Nature 388, 839–840.10.1038/42166Search in Google Scholar PubMed

Toba, S., Jin, M., Yamada, M., Kumamoto, K., Matsumoto, S., Yasunaga, T., Fukunaga, Y., Miyazawa, A., Fujita, S., Itoh, K., et al. (2017). Alpha-synuclein facilitates to form short unconventional microtubules that have a unique function in the axonal transport. Sci. Rep. 7, 16386.10.1038/s41598-017-15575-3Search in Google Scholar PubMed PubMed Central

Trempe, J.F., Sauvé, V., Grenier, K., Seirafi, M., Tang, M.Y., Ménade, M., Al-Abdul-Wahid, S., Krett, J., Wong, K., Kozlov, G., et al. (2013). Structure of parkin reveals mechanisms for ubiquitin ligase activation. Science 340, 1451–1455.10.1126/science.1237908Search in Google Scholar PubMed

Tsika, E. and Moore, D.J. (2013). Contribution of GTPase activity to LRRK2-associated Parkinson disease. Small GTPases 4, 164–170.10.4161/sgtp.25130Search in Google Scholar PubMed PubMed Central

Uversky, V.N. (2002). What does it mean to be natively unfolded? Eur. J. Biochem. 269, 2–12.10.1046/j.0014-2956.2001.02649.xSearch in Google Scholar PubMed

Vitte, J., Traver, S., Maues De Paula, A., Lesage, S., Rovelli, G., Corti, O., Duyckaerts, C., and Brice, A. (2010). Leucine-rich repeat kinase 2 is associated with the endoplasmic reticulum in dopaminergic neurons and accumulates in the core of Lewy bodies in Parkinson disease. J. Neuropathol. Exp. Neurol. 69, 959–972.10.1097/NEN.0b013e3181efc01cSearch in Google Scholar PubMed

Wallings, R., Manzoni, C., and Bandopadhyay, R. (2015). Cellular processes associated with LRRK2 function and dysfunction. FEBS J. 282, 2806–2826.10.1111/febs.13305Search in Google Scholar PubMed PubMed Central

Wauer, T. and Komander, D. (2013). Structure of the human Parkin ligase domain in an autoinhibited state. EMBO J. 32, 2099–2112.10.1038/emboj.2013.125Search in Google Scholar PubMed PubMed Central

Wauters, L., Versées, W., and Kortholt, A. (2019). Roco proteins: GTPases with a baroque structure and mechanism. Int. J. Mol. Sci. 20, 147.10.3390/ijms20010147Search in Google Scholar PubMed PubMed Central

West, A.B., Moore, D.J., Biskup, S., Bugayenko, A., Smith, W.W., Ross, C.A., Dawson, V.L., and Dawson, T.M. (2005). Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl. Acad. Sci. USA 102, 16842–16847.10.1073/pnas.0507360102Search in Google Scholar PubMed PubMed Central

Xu, Z., Schaedel, L., Portran, D., Aguilar, A., Gaillard, J., Marinkovich, M.P., Théry, M., and Nachury, M.V. (2017). Microtubules acquire resistance from mechanical breakage through intralumenal acetylation. Science 356, 328–332.10.1126/science.aai8764Search in Google Scholar PubMed PubMed Central

Yang, F., Jiang, Q., Zhao, J., Ren, Y., Sutton, M.D., and Feng, J. (2005). Parkin stabilizes microtubules through strong binding mediated by three independent domains. J. Biol. Chem. 280, 17154–17162.10.1074/jbc.M500843200Search in Google Scholar PubMed

Yoshino, H., Hirano, M., Stoessl, A.J., Imamichi, Y., Ikeda, A., Li, Y., Funayama, M., Yamada, I., Nakamura, Y., Sossi, V., et al. (2017). Homozygous α-synuclein p.A53V in familial Parkinson’s disease. Neurobiol. Aging 57, 248.e7–e248.e12.10.1016/j.neurobiolaging.2017.05.022Search in Google Scholar PubMed

Zarranz, J.J., Alegre, J., Gómez-Esteban, J.C., Lezcano, E., Ros, R., Ampuero, I., Vidal, L., Hoenicka, J., Rodriguez, O., Atarés, B., et al. (2004). The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 55, 164–173.10.1002/ana.10795Search in Google Scholar PubMed

Zhang, Y., Gao, J., Chung, K.K., Huang, H., Dawson, V.L., and Dawson, T.M. (2000). Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc. Natl. Acad. Sci. USA 97, 13354–13359.10.1073/pnas.240347797Search in Google Scholar PubMed PubMed Central

Zhang, C.W., Hang, L., Yao, T.P., and Lim, K.L. (2016). Parkin regulation and neurodegenerative disorders. Front. Aging Neurosci. 7, 248.10.3389/fnagi.2015.00248Search in Google Scholar PubMed PubMed Central

Zhang, X., Gao, F., Wang, D., Li, C., Fu, Y., He, W., and Zhang, J. (2018). Tau pathology in Parkinson’s disease. Front. Neurol. 9, 809.10.3389/fneur.2018.00809Search in Google Scholar PubMed PubMed Central

Zhou, R.M., Huang, Y.X., Li, X.L., Chen, C., Shi, Q., Wang, G.R., Tian, C., Wang, Z.Y., Jing, Y.Y., Gao, C., et al. (2010). 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, 3183–3192.10.1007/s11033-009-9899-2Search in Google Scholar PubMed

Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R.J., Calne, D.B., et al. (2004). Mutations in LRRK2 cause autosomal-dominant Parkinsonism with pleomorphic pathology. Neuron 44, 601–607.10.1016/j.neuron.2004.11.005Search in Google Scholar PubMed

Received: 2019-01-31
Accepted: 2019-06-24
Published Online: 2019-07-19
Published in Print: 2019-08-27

©2019 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 22.2.2024 from
Scroll to top button