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Microtubule Destabilization Paves the Way to Parkinson’s Disease

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Abstract

Microtubules are dynamic structures normally associated to the cell division, during which they form the mitotic spindle, as well as to the initial phases of specification and polarization of various cell types, including neurons. Although microtubules could have a role in the death of many cells and tissues, the microtubule-based degenerative mechanisms have been poorly investigated; nevertheless, during the last two decades, many clues have been accumulated suggesting the importance of the microtubule system during neurodegeneration. Thus, the aim of this review is to analyse how the changes of the microtubule cytoskeleton, in terms of organization and dynamics, as well as the failure of the microtubule-dependent neuronal processes, as axonal transport, may play a pivotal role in the chain of events leading to Parkinson’s disease. Last but not least, since disease-modifying or neuroprotective strategies are a clinical priority in Parkinson’s disease, we will also present the hints about the concrete possibility of a microtubule-targeted therapy, which would have the potentiality to block the running degenerative events and to prompt the regeneration of the lost tissues.

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References

  1. Cajal SR (1906) Nobel lecture: the structure and connexions of neurons. From Nobel Lectures, Physiology or Medicine 1901-1921, Elsevier Publishing Company, Amsterdam,1967

  2. Coles CH, Bradke F (2015) Coordinating neuronal actin-microtubule dynamics. Curr Biol 25(15):R677–91. doi:10.1016/j.cub.2015.06.020

    Article  CAS  PubMed  Google Scholar 

  3. Tischfield MA, Cederquist GY, Gupta ML Jr, Engle EC (2011) Phenotypic spectrum of the tubulin-related disorders and functional implications of disease-causing mutations. Curr Opin Genet Dev 21(3):286–94. doi:10.1016/j.gde.2011.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Millecamps S, Julien JP (2013) Axonal transport deficits and neurodegenerative diseases. Nat Rev Neurosci 14(3):161–76. doi:10.1038/nrn3380

    Article  CAS  PubMed  Google Scholar 

  5. Smith BN, Ticozzi N, Fallini C, Gkazi AS, Topp S, Kenna KP, Scotter EL, Kost J et al (2014) Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron 84(2):324–31. doi:10.1016/j.neuron.2014.09.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Niwa S, Takahashi H, Hirokawa N (2013) β-Tubulin mutations that cause severe neuropathies disrupt axonal transport. EMBO J 32(10):1352–64. doi:10.1038/emboj.2013.59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Baas PW, Ahmad FJ (2013) Beyond taxol: microtubule-based treatment of disease and injury of the nervous system. Brain 136(Pt 10):2937–51. doi:10.1093/brain/awt153

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sato M, Schwartz WH, Selden SC, Pollard TD (1988) Mechanical properties of brain tubulin and microtubules. J Cell Biol 106(4):1205–11

    Article  CAS  PubMed  Google Scholar 

  9. Mitchison T, Kirschner M (1984) Dynamic instability of microtubule growth. Nature 312(5991):237–42

    Article  CAS  PubMed  Google Scholar 

  10. Kapitein LC, Hoogenraad CC (2015) Building the neuronal microtubule cytoskeleton. Neuron 87(3):492–506. doi:10.1016/j.neuron.2015.05.046

    Article  CAS  PubMed  Google Scholar 

  11. Baas PW, Deitch JS, Black MM, Banker GA (1988) Polarity orientation of microtubules in hippocampal neurons: uniformity in the axon and nonuniformity in the dendrite. Proc Natl Acad Sci U S A 85(21):8335–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wai Yau K, Schatzle P, Tortosa E, Pages S, Holtmaat A, Kapitein LC, Hoogenraad CC (2016) Dendrites In vitro and in vivo contain microtubules of opposite polarity and axon formation correlates with uniform plus-end-out microtubule orientation. J Neurosci 36(4):1071–1085. doi:10.1523/JNEUROSCI.2430-15.2016

    Article  CAS  Google Scholar 

  13. Kwan AC, Dombeck DA, Webb WW (2008) Polarized microtubule arrays in apical dendrites and axons. Proc Natl Acad Sci U S A 105(32):11370–5. doi:10.1073/pnas.0805199105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kleele T, Marinković P, Williams PR, Stern S, Weigand EE, Engerer P, Naumann R, Hartmann J et al (2014) An assay to image neuronal microtubule dynamics in mice. Nat Commun 5:4827. doi:10.1038/ncomms5827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kapitein LC, Schlager MA, Kuijpers M, Wulf PS, van Spronsen M, MacKintosh FC, Hoogenraad CC (2009) Mixed microtubules steer dynein-driven cargo transport into dendrites. Curr Biol 20(4):290–9. doi:10.1016/j.cub.2009.12.052

    Article  CAS  Google Scholar 

  16. McCarthy A, Lonergan R, Olszewska DA, O’Dowd S, Cummins G, Magennis B, Fallon EM, Pender N et al (2015) Closing the tau loop: the missing tau mutation. Brain 38(Pt 10):3100–9. doi:10.1093/brain/awv234

    Article  Google Scholar 

  17. Zempel H, Mandelkow E (2014) Lost after translation: missorting of Tau protein and consequences for Alzheimer disease. Trends Neurosci 37(12):721–32. doi:10.1016/j.tins.2014.08.004

    Article  CAS  PubMed  Google Scholar 

  18. Evans KJ, Gomes ER, Reisenweber SM, Gundersen GG, Lauring B (2005) Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing. J Cell Biol 168(4):599–606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Janke C (2014) The tubulin code: molecular components, readout mechanisms, and functions. J Cell Biol 206(4):461–72. doi:10.1083/jcb.201406055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Paturle-Lafanechère L, Manier M, Trigault N, Pirollet F, Mazarguil H, Job D (1994) Accumulation of delta 2-tubulin, a major tubulin variant that cannot be tyrosinated, in neuronal tissues and in stable microtubule assemblies. J Cell Sci 107(Pt 6):1529–43

    PubMed  Google Scholar 

  21. Szyk A, Deaconescu AM, Spector J, Goodman B, Valenstein ML, Ziolkowska NE, Kormendi V, Grigorieff N et al (2014) Molecular basis for age-dependent microtubule acetylation by tubulin acetyltransferase. Cell 157(6):1405–15. doi:10.1016/j.cell.2014.03.061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Khawaja S, Gundersen GG, Bulinski JC (1988) Enhanced stability of microtubules enriched in detyrosinated tubulin is not a direct function of detyrosination level. J Cell Biol 106(1):141–9

    Article  CAS  PubMed  Google Scholar 

  23. Peris L, Wagenbach M, Lafanechère L, Brocard J, Moore AT, Kozielski F, Job D, Wordeman L et al (2009) Motor-dependent microtubule disassembly driven by tubulin tyrosination. J Cell Biol 185(7):1159–66. doi:10.1083/jcb.200902142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sharp DJ, Ross JL (2012) Microtubule-severing enzymes at the cutting edge. J Cell Sci 125(Pt 11):2561–9. doi:10.1242/jcs.101139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Reed NA, Cai D, Blasius TL, Jih GT, Meyhofer E, Gaertig J, Verhey KJ (2006) Microtubule acetylation promotes kinesin-1 binding and transport. Curr Biol 16(21):2166–72

    Article  CAS  PubMed  Google Scholar 

  26. Dunn S, Morrison EE, Liverpool TB, Molina-París C, Cross RA, Alonso MC, Peckham M (2008) Differential trafficking of Kif5c on tyrosinated and detyrosinated microtubules in live cells. J Cell Sci 121(Pt 7):1085–95. doi:10.1242/jcs.026492

    Article  CAS  PubMed  Google Scholar 

  27. Rogowski K, van Dijk J, Magiera MM, Bosc C, Deloulme JC, Bosson A, Peris L, Gold ND et al (2010) A family of protein-deglutamylating enzymes associated with neurodegeneration. Cell 143(4):564–78. doi:10.1016/j.cell.2010.10.014

    Article  CAS  PubMed  Google Scholar 

  28. Prota AE, Magiera MM, Kuijpers M, Bargsten K, Frey D, Wieser M, Jaussi R, Hoogenraad CC et al (2013) Structural basis of tubulin tyrosination by tubulin tyrosine ligase. J Cell Biol 200(3):259–70. doi:10.1083/jcb.201211017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Song W, Cho Y, Watt D, Cavalli V (2015) Tubulin-tyrosine ligase (TTL)-mediated increase in tyrosinated α-tubulin in injured axons is required for retrograde injury signaling and axon regeneration. J Biol Chem 290(23):14765–75. doi:10.1074/jbc.M114.622753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Marcos S, Moreau J, Backer S, Job D, Andrieux A, Bloch-Gallego E (2009) Tubulin tyrosination is required for the proper organization and pathfinding of the growth cone. PLoS One 4(4):e5405. doi:10.1371/journal.pone.0005405

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Gozes I, Sweadner KJ (1981) Multiple tubulin forms are expressed by a single neurone. Nature 294(5840):477–80

    Article  CAS  PubMed  Google Scholar 

  32. Gozes I, Littauer UZ (1978) Tubulin microheterogeneity increases with rat brain maturation. Nature 276(5686):411–3

    Article  CAS  PubMed  Google Scholar 

  33. Lewis SA, Tian G, Cowan NJ (1997) The alpha- and beta-tubulin folding pathways. Trends Cell Biol 7(12):479–84

    Article  CAS  PubMed  Google Scholar 

  34. Vemu A, Atherton J, Spector JO, Szyk A, Moores CA, Roll-Mecak A (2016) Structure and Dynamics of Single-isoform Recombinant Neuronal Human Tubulin. J Biol Chem. doi: 10.1074/jbc.C116.731133

  35. Sirajuddin M, Rice LM, Vale RD (2014) Regulation of microtubule motors by tubulin isotypes and post-translational modifications. Nat Cell Biol 16(4):335–44. doi:10.1038/ncb2920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Schaedel L, John K, Gaillard J, Nachury MV, Blanchoin L, Théry M (2015) Microtubules self-repair in response to mechanical stress. Nat Mater 14(11):1156–63. doi:10.1038/nmat4396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gardner MK, Zanic M, Gell C, Bormuth V, Howard J (2011) Depolymerizing kinesins Kip3 and MCAK shape cellular microtubule architecture by differential control of catastrophe. Cell 147(5):1092–103. doi:10.1016/j.cell.2011.10.037

    Article  CAS  PubMed  Google Scholar 

  38. Bowne-Anderson H, Zanic M, Kauer M, Howard J (2013) Microtubule dynamic instability: a new model with coupled GTP hydrolysis and multistep catastrophe. Bioessays 35(5):452–61. doi:10.1002/bies.201200131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Coombes CE, Yamamoto A, Kenzie MR, Odde DJ, Gardner MK (2013) Evolving tip structures can explain age-dependent microtubule catastrophe. Curr Biol 23(14):1342–8. doi:10.1016/j.cub.2013.05.059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, Hirsch EC, Farrer M et al (2010) Missing pieces in the Parkinson’s disease puzzle. Nat Med 16(6):653–61. doi:10.1038/nm.2165

    Article  CAS  PubMed  Google Scholar 

  41. Klingelhoefer L, Reichmann H (2015) Pathogenesis of Parkinson disease-the gut-brain axis and environmental factors. Nat Rev Neurol 11(11):625–36. doi:10.1038/nrneurol.2015.197

    Article  CAS  PubMed  Google Scholar 

  42. Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909

    Article  CAS  PubMed  Google Scholar 

  43. Pissadaki EK, Bolam JP (2013) The energy cost of action potential propagation in dopamine neurons: clues to susceptibility in Parkinson’s disease. Front Comput Neurosci 13. doi: 10.3389/fncom.2013.00013

  44. Hunn BH, Cragg SJ, Bolam JP, Spillantini MG, Wade-Martins R (2015) Impaired intracellular trafficking defines early Parkinson’s disease. Trends Neurosci 38(3):178–88. doi:10.1016/j.tins.2014.12.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Coleman M (2005) Axon degeneration mechanisms: commonality amid diversity. Nat Rev Neurosci 6(11):889–98

    Article  CAS  PubMed  Google Scholar 

  46. Zhai Q, Wang J, Kim A, Liu Q, Watts R, Hoopfer E, Mitchison T, Luo L et al (2003) Involvement of the ubiquitin-proteasome system in the early stages of Wallerian degeneration. Neuron 39(2):217–25

    Article  CAS  PubMed  Google Scholar 

  47. Ertürk A, Hellal F, Enes J, Bradke F (2007) Disorganized microtubules underlie the formation of retraction bulbs and the failure of axonal regeneration. J Neurosci 27(34):9169–80. doi:10.1523/JNEUROSCI.0612-07.2007

    Article  PubMed  CAS  Google Scholar 

  48. Feng J (2006) Microtubule: a common target for parkin and Parkinson’s disease toxins. Neuroscientist 12(6):469–76. doi:10.1177/1073858406293853

    Article  CAS  PubMed  Google Scholar 

  49. Cappelletti G, Casagrande F, Calogero A, De Gregorio C, Pezzoli G, Cartelli D (2015) Linking microtubules to Parkinson’s disease: the case of parkin. Biochem Soc Trans 43(2):292–6. doi:10.1042/BST20150007

    Article  CAS  PubMed  Google Scholar 

  50. Lindahl PE, Oberg KE (1961) The effect of rotenone on respiration and its point of attack. Exp Cell Res 23:228–37

    Article  CAS  PubMed  Google Scholar 

  51. Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci 36(26):2503–8

    Article  CAS  PubMed  Google Scholar 

  52. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276(5321):2045–7

    Article  CAS  PubMed  Google Scholar 

  53. Marshall LE, Himes RH (1978) Rotenone inhibition of tubulin self-assembly. Biochim Biophys Acta 543(4):590–4

    Article  CAS  PubMed  Google Scholar 

  54. Cappelletti G, Pedrotti B, Maggioni MG, Maci R (2001) Microtubule assembly is directly affected by MPP(+)in vitro. Cell Biol Int 25(10):981–4

    Article  CAS  PubMed  Google Scholar 

  55. Choi WS, Kruse SE, Palmiter RD, Xia Z (2008) Mitochondrial complex I inhibition is not required for dopaminergic neuron death induced by rotenone, MPP+, or paraquat. Proc Natl Acad Sci U S A 105(39):15136–41. doi:10.1073/pnas.0807581105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ren Y, Liu W, Jiang H, Jiang Q, Feng J (2005) Selective vulnerability of dopaminergic neurons to microtubule depolymerization. J Biol Chem 280(40):34105–12

    Article  CAS  PubMed  Google Scholar 

  57. Liang Y, Li S, Wen C, Zhang Y, Guo Q, Wang H, Su B (2008) Intrastriatal injection of colchicine induces striatonigral degeneration in mice. J Neurochem 106(4):1815–27. doi:10.1111/j.1471-4159.2008.05526.x

    Article  CAS  PubMed  Google Scholar 

  58. Cappelletti G, Surrey T, Maci R (2005) The parkinsonism producing neurotoxin MPP+ affects microtubule dynamics by acting as a destabilising factor. FEBS Lett 579(21):4781–6. doi:10.1016/j.febslet.2005.07.058

    Article  CAS  PubMed  Google Scholar 

  59. Cartelli D, Ronchi C, Maggioni MG, Rodighiero S, Giavini E, Cappelletti G (2010) Microtubule dysfunction precedes transport impairment and mitochondria damage in MPP+-induced neurodegeneration. J Neurochem 115(1):247–58. doi:10.1111/j.1471-4159.2010.06924.x

    Article  CAS  PubMed  Google Scholar 

  60. Cartelli D, Casagrande F, Busceti CL, Bucci D, Molinaro G, Traficante A, Passarella D, Giavini E et al (2013) Microtubule alterations occur early in experimental parkinsonism and the microtubule stabilizer epothilone D is neuroprotective. Sci Rep 3:1837. doi:10.1038/srep01837

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Shemesh OA, Erez H, Ginzburg I, Spira ME (2008) Tau-induced traffic jams reflect organelles accumulation at points of microtubule polar mismatching. Traffic 9(4):458–71. doi:10.1111/j.1600-0854.2007.00695.x

    Article  CAS  PubMed  Google Scholar 

  62. Patel VP, Chu CT (2014) Decreased SIRT2 activity leads to altered microtubule dynamics in oxidatively-stressed neuronal cells: implications for Parkinson’s disease. Exp Neurol 257:170–81. doi:10.1016/j.expneurol.2014.04.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Escobar-Khondiker M, Höllerhage M, Muriel MP, Champy P, Bach A, Depienne C, Respondek G, Yamada ES et al (2007) Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons. J Neurosci 27(29):7827–37. doi:10.1523/JNEUROSCI.1644-07.2007

    Article  CAS  PubMed  Google Scholar 

  64. Kim-Han JS, Antenor-Dorsey JA, O’Malley KL (2011) The parkinsonian mimetic, MPP+, specifically impairs mitochondrial transport in dopamine axons. J Neurosci 31(19):7212–21. doi:10.1523/JNEUROSCI.0711-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Shen J (2004) Protein kinases linked to the pathogenesis of Parkinson’s disease. Neuron 44(4):575–7

    Article  CAS  PubMed  Google Scholar 

  66. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y et al (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392(6676):605–8

    Article  CAS  PubMed  Google Scholar 

  67. Law BM, Spain VA, Leinster VH, Chia R, Beilina A, Cho HJ, Taymans JM, Urban MK et al (2014) A direct interaction between leucine-rich repeat kinase 2 and specific β-tubulin isoforms regulates tubulin acetylation. J Biol Chem 289(2):895–908. doi:10.1074/jbc.M113.507913

    Article  CAS  PubMed  Google Scholar 

  68. 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(5):1514–22. doi:10.1111/j.1471-4159.2009.06235.x

    Article  CAS  PubMed  Google Scholar 

  69. Cartelli D, Goldwurm S, Casagrande F, Pezzoli G, Cappelletti G (2012) Microtubule destabilization is shared by genetic and idiopathic Parkinson's disease patient fibroblasts. PLoS One 7(5):e37467. doi:10.1371/journal.pone.0037467

  70. Godena VK, Brookes-Hocking N, Moller A, Shaw G, Oswald M, Sancho RM, Miller CC, Whitworth AJ et al (2014) Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. Nat Commun 5:5245. doi:10.1038/ncomms6245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Schwab AJ, Ebert AD (2015) Neurite aggregation and calcium dysfunction in iPSC-derived sensory neurons with Parkinson's disease-related LRRK2 G2019S mutation. Stem Cell Reports 5(6):1039–52. doi:10.1016/j.stemcr.2015.11.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ren Y, Zhao J, Feng J (2003) Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation. J Neurosci 23(8):3316–24

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Yang F, Jiang Q, Zhao J, Ren Y, Sutton MD, Feng J (2005) Parkin stabilizes microtubules through strong binding mediated by three independent domains. J Biol Chem 280(17):17154–62

    Article  CAS  PubMed  Google Scholar 

  74. Ren Y, Jiang H, Yang F, Nakaso K, Feng J (2009) Parkin protects dopaminergic neurons against microtubule-depolymerizing toxins by attenuating microtubule-associated protein kinase activation. J Biol Chem 284(6):4009–17. doi:10.1074/jbc.M806245200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ren Y, Jiang H, Hu Z, Fan K, Wang J, Janoschka S, Wang X, Ge S et al (2015) Parkin mutations reduce the complexity of neuronal processes in iPSC-derived human neurons. Stem Cells 33(1):68–78. doi:10.1002/stem.1854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Alim MA, Hossain MS, Arima K, Takeda K, Izumiyama Y, Nakamura M, Kaji H, Shinoda T et al (2002) Tubulin seeds alpha-synuclein fibril formation. J Biol Chem 277(3):2112–7

    Article  CAS  PubMed  Google Scholar 

  77. Esteves AR, Arduíno DM, Swerdlow RH, Oliveira CR, Cardoso SM (2010) Microtubule depolymerization potentiates alpha-synuclein oligomerization. Front Aging Neurosci 1:5. doi:10.3389/neuro.24.005.2009, eCollection 2010

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Nakayama K, Suzuki Y, Yazawa I (2010) Microtubule depolymerization suppresses alpha-synuclein accumulation in a mouse model of multiple system atrophy. Am J Pathol 174(4):1471–80. doi:10.2353/ajpath.2009.080503

    Article  CAS  Google Scholar 

  79. Zhou RM, Huang YX, Li XL, Chen C, Shi Q, Wang GR, Tian C, Wang ZY 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(7):3183–92. doi:10.1007/s11033-009-9899-2

    Article  CAS  PubMed  Google Scholar 

  80. Prots I, Veber V, Brey S, Campioni S, Buder K, Riek R, Böhm KJ, Winner B (2013) α-Synuclein oligomers impair neuronal microtubule-kinesin interplay. J Biol Chem 288(30):21742–54. doi:10.1074/jbc.M113.451815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Alim MA, Ma QL, Takeda K, Aizawa T, Matsubara M, Nakamura M, Asada A, Saito T et al (2004) Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein. J Alzheimers Dis 6(4):435–42, discussion 443-9

    Article  PubMed  Google Scholar 

  82. Chen L, Jin J, Davis J, Zhou Y, Wang Y, Liu J, Lockhart PJ, Zhang J (2007) Oligomeric alpha-synuclein inhibits tubulin polymerization. Biochem Biophys Res Commun 356(3):548–53

    Article  CAS  PubMed  Google Scholar 

  83. Cartelli D, Aliverti A, Barbiroli A, Santambrogio C, Ragg EM, Casagrande FVM, Cantele F, Beltramone S et al (2016) α-Synuclein is a novel microtubule dynamase. Sci Rep 6:33289. doi:10.1038/srep33289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D, Rice S, Steen J et al (2011) PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147(4):893–906. doi:10.1016/j.cell.2011.10.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sheng C, Heng X, Zhang G, Xiong R, Li H, Zhang S, Chen S (2013) DJ-1 deficiency perturbs microtubule dynamics and impairs striatal neurite outgrowth. Neurobiol Aging 34(2):489–98. doi:10.1016/j.neurobiolaging.2012.04.008

    Article  CAS  PubMed  Google Scholar 

  86. Galloway PG, Grundke-Iqbal I, Iqbal K, Perry G (1988) Lewy bodies contain epitopes both shared and distinct from Alzheimer neurofibrillary tangles. J Neuropathol Exp Neurol 47(6):654–63

    Article  CAS  PubMed  Google Scholar 

  87. Lewy FH (1912) Paralysis agitans I. Pathologische anatomie. In: Lewandowsky M (ed) Handbuch der neurologie. Springer, Berlin, pp 920–933

    Google Scholar 

  88. Ross CA, Poirier MA (2005) Opinion: what is the role of protein aggregation in neurodegeneration? Nat Rev Mol Cell Biol 6(11):891–8

    Article  CAS  PubMed  Google Scholar 

  89. Power JH, Barnes OL, Chegini F (2015) Lewy bodies and the mechanisms of neuronal cell death in parkinson's disease and dementia with Lewy bodies. Brain Pathol 15. doi: 10.1111/bpa.12344

  90. Chu Y, Morfini GA, Langhamer LB, He Y, Brady ST, Kordower JH (2012) Alterations in axonal transport motor proteins in sporadic and experimental Parkinson's disease. Brain 135(Pt 7):2058–73. doi:10.1093/brain/aws133

    Article  PubMed  PubMed Central  Google Scholar 

  91. Chung CY, Koprich JB, Siddiqi H, Isacson O (2009) Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV alpha-synucleinopathy. J Neurosci 29(11):3365–73. doi:10.1523/JNEUROSCI.5427-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Akella JS, Wloga D, Kim J, Starostina NG, Lyons-Abbott S, Morrissette NS, Dougan ST, Kipreos ET et al (2010) MEC-17 is an alpha-tubulin acetyltransferase. Nature 467(7312):218–22. doi:10.1038/nature09324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF et al (2002) HDAC6 is a microtubule-associated deacetylase. Nature 417(6887):455–8

    Article  CAS  PubMed  Google Scholar 

  94. Simões-Pires C, Zwick V, Nurisso A, Schenker E, Carrupt PA, Cuendet M (2013) HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs? Mol Neurodegener 8:7. doi:10.1186/1750-1326-8-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Gobrecht P, Andreadaki A, Diekmann H, Heskamp A, Leibinger M, Fischer D (2016) Promotion of functional nerve regeneration by inhibition of microtubule detyrosination. J Neurosci 36(14):3890–3902

    Article  CAS  PubMed  Google Scholar 

  96. Das V, Sim DA, Miller JH (2014) Effect of taxoid and nontaxoid site microtubule-stabilizing agents on axonal transport of mitochondria in untransfected and ECFP-htau40-transfected rat cortical neurons in culture. J Neurosci Res 92(9):1155–66. doi:10.1002/jnr.23394

    Article  CAS  PubMed  Google Scholar 

  97. Katsetos CD, Dráber P (2012) Tubulins as therapeutic targets in cancer: from bench to bedside. Curr Pharm Des 8(19):2778–92

    Article  Google Scholar 

  98. Brunden KR, Zhang B, Carroll J, Yao Y, Potuzak JS, Hogan AM, Iba M, James MJ et al (2010) Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J Neurosci 30(41):13861–6. doi:10.1523/JNEUROSCI.3059-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhang B, Carroll J, Trojanowski JQ, Yao Y, Iba M, Potuzak JS, Hogan AM, Xie SX et al (2012) The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J Neurosci 32(11):3601–11. doi:10.1523/JNEUROSCI.4922-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hellal F, Hurtado A, Ruschel J, Flynn KC, Laskowski CJ, Umlauf M, Kapitein LC, Strikis D et al (2011) Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science 331(6019):928–31. doi:10.1126/science.1201148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ruschel J, Hellal F, Flynn KC, Dupraz S, Elliott DA, Tedeschi A, Bates M, Sliwinski C et al (2015) Axonal regeneration. Systemic administration of epothilone B promotes axon regeneration after spinal cord injury. Science 348(6232):347–52. doi:10.1126/science.aaa2958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Fleming SM, Mulligan CK, Richter F, Mortazavi F, Lemesre V, Frias C, Zhu C, Stewart A et al (2011) A pilot trial of the microtubule-interacting peptide (NAP) in mice overexpressing alpha-synuclein shows improvement in motor function and reduction of alpha-synuclein inclusions. Mol Cell Neurosci 46(3):597–606. doi:10.1016/j.mcn.2010.12.011

    Article  CAS  PubMed  Google Scholar 

  103. Magen I, Ostritsky R, Richter F, Zhu C, Fleming SM, Lemesre V, Stewart AJ, Morimoto BH et al (2014) Intranasal NAP (davunetide) decreases tau hyperphosphorylation and moderately improves behavioral deficits in mice overexpressing α-synuclein. Pharmacol Res Perspect 2(5):e00065. doi:10.1002/prp2.65

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Esteves AR, Gozes I, Cardoso SM (2014) The rescue of microtubule-dependent traffic recovers mitochondrial function in Parkinson's disease. Biochim Biophys Acta 1842(1):7–21. doi:10.1016/j.bbadis.2013.10.003

    Article  CAS  PubMed  Google Scholar 

  105. Gozes I, Iram T, Maryanovsky E, Arviv C, Rozenberg L, Schirer Y, Giladi E, Furman-Assaf S (2014) Novel tubulin and tau neuroprotective fragments sharing structural similarities with the drug candidate NAP (davunetide). J Alzheimers Dis 40(Suppl 1):S23–36. doi:10.3233/JAD-131664

    PubMed  Google Scholar 

  106. Pieraccini S, Saladino G, Cappelletti G, Cartelli D, Francescato P, Speranza G, Manitto P, Sironi M (2009) In silico design of tubulin-targeted antimitotic peptides. Nat Chem 8:642–8. doi:10.1038/nchem.401

    Article  CAS  Google Scholar 

  107. Lazzara CA, Kim YH (2015) Potential application of lithium in Parkinson's and other neurodegenerative diseases. Front Neurosci 9:403. doi:10.3389/fnins.2015.00403, eCollection 2015

    Article  PubMed  PubMed Central  Google Scholar 

  108. Williams R, Ryves WJ, Dalton EC, Eickholt B, Shaltiel G, Agam G, Harwood AJ (2004) A molecular cell biology of lithium. Biochem Soc Trans 32(Pt 5):799–802

    Article  CAS  PubMed  Google Scholar 

  109. Wolff J, Sackett DL, Knipling L (1996) Cation selective promotion of tubulin polymerization by alkali metal chlorides. Protein Sci 5(10):2020–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Bhattacharyya B, Wolff J (1976) Stabilization of microtubules by lithium ion. Biochem Biophys Res Commun 73(2):383–90

    Article  CAS  PubMed  Google Scholar 

  111. Nakakura T, Asano-Hoshino A, Suzuki T, Arisawa K, Tanaka H, Sekino Y, Kiuchi Y, Kawai K et al (2015) The elongation of primary cilia via the acetylation of α-tubulin by the treatment with lithium chloride in human fibroblast KD cells. Med Mol Morpho 48(1):44–53. doi:10.1007/s00795-014-0076-x

    Article  CAS  Google Scholar 

  112. Rostovtseva TK, Sheldon KL, Hassanzadeh E, Monge C, Saks V, Bezrukov SM, Sackett DL (2008) Tubulin binding blocks mitochondrial voltage-dependent anion channel and regulates respiration. Proc Natl Acad Sci U S A 105(48):18746–51. doi:10.1073/pnas.0806303105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Maldonado EN, Patnaik J, Mullins MR, Lemasters JJ (2010) Free tubulin modulates mitochondrial membrane potential in cancer cells. Cancer Res 70(24):10192–201. doi:10.1158/0008-5472.CAN-10-2429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors are grateful to all the present and past members of the laboratory for their work, which have contributed in delineating the story here described, as well as for the interesting and stimulating discussions. This work was supported by Fondazione Grigioni per il Morbo di Parkinson, Milan, Italy (to G.C.), and “Dote ricerca”, FSE, Regione Lombardia (to D.C.). The authors apologize for any possible involuntary paper omission.

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  1. Department Biosciences, Università degli Studi di Milano, Via Celoria 26, Milano, 20133, Italy

    D. Cartelli & G. Cappelletti

  2. Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milano, Italy

    G. Cappelletti

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  1. D. Cartelli
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  2. G. Cappelletti
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Correspondence to D. Cartelli.

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Cartelli, D., Cappelletti, G. Microtubule Destabilization Paves the Way to Parkinson’s Disease. Mol Neurobiol 54, 6762–6774 (2017). https://doi.org/10.1007/s12035-016-0188-5

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