Molecular Neurobiology

, Volume 54, Issue 9, pp 6762–6774 | Cite as

Microtubule Destabilization Paves the Way to Parkinson’s Disease

Article

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.

Keywords

Microtubule Neuron health Neurodegeneration Parkinson’s disease Tubulin-targeted therapy 

Notes

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.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

References

  1. 1.
    Cajal SR (1906) Nobel lecture: the structure and connexions of neurons. From Nobel Lectures, Physiology or Medicine 1901-1921, Elsevier Publishing Company, Amsterdam,1967Google Scholar
  2. 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 PubMedCrossRefGoogle Scholar
  3. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Millecamps S, Julien JP (2013) Axonal transport deficits and neurodegenerative diseases. Nat Rev Neurosci 14(3):161–76. doi: 10.1038/nrn3380 PubMedCrossRefGoogle Scholar
  5. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  6. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  7. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Sato M, Schwartz WH, Selden SC, Pollard TD (1988) Mechanical properties of brain tubulin and microtubules. J Cell Biol 106(4):1205–11PubMedCrossRefGoogle Scholar
  9. 9.
    Mitchison T, Kirschner M (1984) Dynamic instability of microtubule growth. Nature 312(5991):237–42PubMedCrossRefGoogle Scholar
  10. 10.
    Kapitein LC, Hoogenraad CC (2015) Building the neuronal microtubule cytoskeleton. Neuron 87(3):492–506. doi: 10.1016/j.neuron.2015.05.046 PubMedCrossRefGoogle Scholar
  11. 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):8335–9PubMedPubMedCentralCrossRefGoogle Scholar
  12. 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 CrossRefGoogle Scholar
  13. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  14. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  15. 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 CrossRefGoogle Scholar
  16. 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 CrossRefGoogle Scholar
  17. 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 PubMedCrossRefGoogle Scholar
  18. 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):599–606PubMedPubMedCentralCrossRefGoogle Scholar
  19. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  20. 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):1529–43PubMedGoogle Scholar
  21. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  22. 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):141–9PubMedCrossRefGoogle Scholar
  23. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  25. 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):2166–72PubMedCrossRefGoogle Scholar
  26. 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 PubMedCrossRefGoogle Scholar
  27. 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 PubMedCrossRefGoogle Scholar
  28. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  29. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  30. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Gozes I, Sweadner KJ (1981) Multiple tubulin forms are expressed by a single neurone. Nature 294(5840):477–80PubMedCrossRefGoogle Scholar
  32. 32.
    Gozes I, Littauer UZ (1978) Tubulin microheterogeneity increases with rat brain maturation. Nature 276(5686):411–3PubMedCrossRefGoogle Scholar
  33. 33.
    Lewis SA, Tian G, Cowan NJ (1997) The alpha- and beta-tubulin folding pathways. Trends Cell Biol 7(12):479–84PubMedCrossRefGoogle Scholar
  34. 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. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  36. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  37. 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 PubMedCrossRefGoogle Scholar
  38. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  39. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  40. 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 PubMedCrossRefGoogle Scholar
  41. 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 PubMedCrossRefGoogle Scholar
  42. 42.
    Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909PubMedCrossRefGoogle Scholar
  43. 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. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Coleman M (2005) Axon degeneration mechanisms: commonality amid diversity. Nat Rev Neurosci 6(11):889–98PubMedCrossRefGoogle Scholar
  46. 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):217–25PubMedCrossRefGoogle Scholar
  47. 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 PubMedCrossRefGoogle Scholar
  48. 48.
    Feng J (2006) Microtubule: a common target for parkin and Parkinson’s disease toxins. Neuroscientist 12(6):469–76. doi: 10.1177/1073858406293853 PubMedCrossRefGoogle Scholar
  49. 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 PubMedCrossRefGoogle Scholar
  50. 50.
    Lindahl PE, Oberg KE (1961) The effect of rotenone on respiration and its point of attack. Exp Cell Res 23:228–37PubMedCrossRefGoogle Scholar
  51. 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):2503–8PubMedCrossRefGoogle Scholar
  52. 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):2045–7PubMedCrossRefGoogle Scholar
  53. 53.
    Marshall LE, Himes RH (1978) Rotenone inhibition of tubulin self-assembly. Biochim Biophys Acta 543(4):590–4PubMedCrossRefGoogle Scholar
  54. 54.
    Cappelletti G, Pedrotti B, Maggioni MG, Maci R (2001) Microtubule assembly is directly affected by MPP(+)in vitro. Cell Biol Int 25(10):981–4PubMedCrossRefGoogle Scholar
  55. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  56. 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):34105–12PubMedCrossRefGoogle Scholar
  57. 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 PubMedCrossRefGoogle Scholar
  58. 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 PubMedCrossRefGoogle Scholar
  59. 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 PubMedCrossRefGoogle Scholar
  60. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  61. 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 PubMedCrossRefGoogle Scholar
  62. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  63. 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 PubMedCrossRefGoogle Scholar
  64. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Shen J (2004) Protein kinases linked to the pathogenesis of Parkinson’s disease. Neuron 44(4):575–7PubMedCrossRefGoogle Scholar
  66. 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):605–8PubMedCrossRefGoogle Scholar
  67. 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 PubMedCrossRefGoogle Scholar
  68. 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 PubMedCrossRefGoogle Scholar
  69. 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. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  71. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Ren Y, Zhao J, Feng J (2003) Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation. J Neurosci 23(8):3316–24PubMedPubMedCentralGoogle Scholar
  73. 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):17154–62PubMedCrossRefGoogle Scholar
  74. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  75. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  76. 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):2112–7PubMedCrossRefGoogle Scholar
  77. 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 2010PubMedPubMedCentralCrossRefGoogle Scholar
  78. 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 CrossRefGoogle Scholar
  79. 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 PubMedCrossRefGoogle Scholar
  80. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  81. 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 443-9PubMedCrossRefGoogle Scholar
  82. 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):548–53PubMedCrossRefGoogle Scholar
  83. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  84. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  85. 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 PubMedCrossRefGoogle Scholar
  86. 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):654–63PubMedCrossRefGoogle Scholar
  87. 87.
    Lewy FH (1912) Paralysis agitans I. Pathologische anatomie. In: Lewandowsky M (ed) Handbuch der neurologie. Springer, Berlin, pp 920–933Google Scholar
  88. 88.
    Ross CA, Poirier MA (2005) Opinion: what is the role of protein aggregation in neurodegeneration? Nat Rev Mol Cell Biol 6(11):891–8PubMedCrossRefGoogle Scholar
  89. 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. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  91. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  92. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  93. 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):455–8PubMedCrossRefGoogle Scholar
  94. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  95. 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):3890–3902PubMedCrossRefGoogle Scholar
  96. 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 PubMedCrossRefGoogle Scholar
  97. 97.
    Katsetos CD, Dráber P (2012) Tubulins as therapeutic targets in cancer: from bench to bedside. Curr Pharm Des 8(19):2778–92CrossRefGoogle Scholar
  98. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  99. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  100. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  101. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  102. 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 PubMedCrossRefGoogle Scholar
  103. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  104. 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 PubMedCrossRefGoogle Scholar
  105. 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 PubMedGoogle Scholar
  106. 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 CrossRefGoogle Scholar
  107. 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 2015PubMedPubMedCentralCrossRefGoogle Scholar
  108. 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):799–802PubMedCrossRefGoogle Scholar
  109. 109.
    Wolff J, Sackett DL, Knipling L (1996) Cation selective promotion of tubulin polymerization by alkali metal chlorides. Protein Sci 5(10):2020–8PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Bhattacharyya B, Wolff J (1976) Stabilization of microtubules by lithium ion. Biochem Biophys Res Commun 73(2):383–90PubMedCrossRefGoogle Scholar
  111. 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 CrossRefGoogle Scholar
  112. 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 PubMedPubMedCentralCrossRefGoogle Scholar
  113. 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 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department BiosciencesUniversità degli Studi di MilanoMilanoItaly
  2. 2.Center of Excellence on Neurodegenerative DiseasesUniversità degli Studi di MilanoMilanoItaly

Personalised recommendations