Advertisement

TPPP/p25: A New Unstructured Protein Hallmarking Synucleinopathies

  • Ferenc Orosz
  • Attila Lehotzky
  • Judit Oláh
  • Judit Ovádi
Chapter
Part of the Focus on Structural Biology book series (FOSB, volume 7)

Abstract

There is increasing evidence that unfolded and misfolded proteins initiate a cascade of pathogenic protein-protein interactions that culminate in neuronal dysfunction. This is a multistep process which results in toxic protein aggregates; thus they are potent targets for development of early diagnosis and of drugs to improve therapies of conformational diseases. The hallmark proteins of these diseases such as Parkinson’s, Alzheimer’s or Huntington’s diseases, are α-synuclein, tau or mutant huntingtin, respectively, which do not have well-defined 3D structures and require protein partners to express their pathological functions. In this paper we review a new unstructured protein denoted Tubulin Polymerization Promoting Protein, TPPP/p25, from the discovery to its enrichment in human pathological inclusions characteristic for synucleinopathies with specific emphasis on its pursuits in single cells. There is a gappy area in the research of unfolded proteins referring to their structure-derived physiological and pathological functions. The studies of TPPP-homologous proteins at different levels of organization, molecular, cellular and tissue levels, rendered possible to reveal some TPPP/p25 specific structural and functional features, in addition to the general items for the role of the unfolded regions of the highly flexible proteins in their physiological and/or pathological functions.

Keywords

Multiple System Atrophy Myelin Basic Protein Tubulin Polymerization Pathological Function Unstructured Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Hlavanda E, Kovács J, Oláh J, Orosz F, Medzihradszky KF, Ovádi J (2002) Brain-specific p25 protein binds to tubulin and microtubules and induces aberrant microtubule assemblies at substoichiometric concentrations. Biochemistry 41:8657–8664PubMedCrossRefGoogle Scholar
  2. 2.
    Takahashi M, Tomizawa K, Ishiguro K, Sato K, Omori A, Sato S, Shiratsuchi A, Uchida T, Imahori K (1991) A novel brain-specific 25 kDa protein (p25) is phosphorylated by a Ser Thr-Pro kinase (TPK-II) from tau protein-kinase fractions. FEBS Lett 289:37–43PubMedCrossRefGoogle Scholar
  3. 3.
    Shiratsuchi A, Sato S, Oomori A, Ishiguro K, Uchida T, Imahori K (1995) cDNA cloning of a novel brain-specific protein p25. Biochim Biophys Acta 1251:66–68PubMedGoogle Scholar
  4. 4.
    Seki N, Hattori A, Sugano S, Suzuki Y, Nakagawara A, Muramatsu M, Hori T, Saito T (1999) A novel human gene whose product shares significant homology with the bovine brain-specific protein p25 on chromosome 5p15.3. J Hum Genet 44:121–122PubMedCrossRefGoogle Scholar
  5. 5.
    Tirián L, Hlavanda E, Oláh J, Horváth I, Orosz F, Szabó B, Kovács J, Szabad J, Ovádi J (2003) TPPP/p25 promotes tubulin assemblies and blocks mitotic spindle formation. Proc Natl Acad Sci USA 100:13976–13981PubMedCrossRefGoogle Scholar
  6. 6.
    Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai L-H (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615–622PubMedCrossRefGoogle Scholar
  7. 7.
    Zhang Z, Wu CQ, Huang W, Wang S, Zhao EP, Huang QS, Xie Y, Mao YM (2002) A novel human gene whose product shares homology with bovine brain-specific protein p25 is expressed in fetal brain but not in adult brain. J Hum Genet 47:266–268PubMedCrossRefGoogle Scholar
  8. 8.
    Vincze O, Tőkési N, Oláh J, Hlavanda E, Zotter Á, Horváth I, Lehotzky A, Tirián L, Medzihradszky KF, Kovács J et al. (2006) Tubulin polymerization promoting proteins (TPPPs): members of a new family with distinct structures and functions. Biochemistry 45:13818–13826PubMedCrossRefGoogle Scholar
  9. 9.
    Lai CH CC, Ch’ang LY, Liu CS, Lin W (2000) Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome Res 10:703–713PubMedCrossRefGoogle Scholar
  10. 10.
    Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF et al. (2002) Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci USA 99:16899–16903PubMedCrossRefGoogle Scholar
  11. 11.
    Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW et al. (2001) Intrinsically disordered protein. J Mol Graph Model 19:26–59PubMedCrossRefGoogle Scholar
  12. 12.
    Uversky VN (2002) Natively unfolded proteins: a point where biology waits for physics. Protein Sci 11:739–756PubMedCrossRefGoogle Scholar
  13. 13.
    Tompa P (2002) Intrinsically unstructured proteins. Trends Biochem Sci 27:527–533PubMedCrossRefGoogle Scholar
  14. 14.
    Fuxreiter M, Simon I, Friedrich P, Tompa P (2004) Preformed structural elements feature in partner recognition by intrinsically unstructured proteins. J Mol Biol 338:1015–1026PubMedCrossRefGoogle Scholar
  15. 15.
    Li X, Romero P, Rani M, Dunker AK, Obradovic Z (1999) Predicting protein disorder for N-, C-, and internal regions. Genome Inform Ser Workshop Genome Inform 10:30–40PubMedGoogle Scholar
  16. 16.
    Romero P, Obradovic Z, Li X, Garner EC, Brown CJ, Dunker AK (2001) Sequence complexity of disordered protein. Proteins 42:38–48PubMedCrossRefGoogle Scholar
  17. 17.
    Ward JJ, Sodhi JS, McGuffin LJ, Buxton BF, Jones DT (2004) Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol 337:635–645PubMedCrossRefGoogle Scholar
  18. 18.
    Dosztányi Z, Csizmók V, Tompa P, Simon I (2005) The pairwise energy content estimated from amino acid composition discriminates between folded and intrinsically unstructured proteins. J Mol Biol 347:827–839.PubMedCrossRefGoogle Scholar
  19. 19.
    Dosztányi Z, Csizmók V, Tompa P, Simon I (2005) IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. Bioinformatics 21:3433–3434PubMedCrossRefGoogle Scholar
  20. 20.
    Dunker AK, Brown CJ, Obradovic Z (2002) Identification and functions of usefully disordered proteins. Adv Protein Chem 62:25–49PubMedCrossRefGoogle Scholar
  21. 21.
    Dosztányi Z, Fiser A, Simon I, (1997) Stabilization centers in proteins: identification, characterization and predictions. J Mol Biol 272:597–612PubMedCrossRefGoogle Scholar
  22. 22.
    Orosz F, Kovács GG, Lehotzky A, Oláh J, Vincze O, Ovádi J (2004) TPPP/p25: from unfolded protein to misfolding disease: prediction and experiments. Biol Cell 96:701–711PubMedCrossRefGoogle Scholar
  23. 23.
    Kovacs GG, László L, Kovács J, Jensen PH, Lindersson E, Botond G, Molnár T, Perczel A, Hudecz F, Mező G et al. (2004) Natively unfolded tubulin polymerization promoting protein TPPP/p25 is a common marker of alpha-synucleinopathies. Neurobiol Dis 17:155–162PubMedCrossRefGoogle Scholar
  24. 24.
    Otzen DE, Lundvig DMS, Wimmer R, Nielsen LH, Pedersen JR, Jensen PH (2005) p25 alpha is flexible but natively folded and binds tubulin with oligomeric stoichiometry. Prot Sci 14:1396–1409CrossRefGoogle Scholar
  25. 25.
    Aramini JM, Rossi P, Shastry R, Nwosu C, Cunningham K, Xiao R, Liu J, Baran MC, Rajan PK, Acton TB et al. (2007) Solution NMR structure of Tubulin polymerization-promoting protein family member 3 from Homo sapiens. http://www.pdb.org/pdb/explore/ explore.do?structureId=2JRFGoogle Scholar
  26. 26.
    Hua QX, Jia WH, Bullock BP, Habener JF, Weiss MA (1998) Transcriptional activator–coactivator recognition: nascent folding of a kinase-inducible transactivation domain predicts its structure on coactivator binding. Biochemistry 37:5858–5866PubMedCrossRefGoogle Scholar
  27. 27.
    Monleon D, Chiang Y, Aramini JM, Swapna GV, Macapagal D, Gunsalus KC, Kim S, Szyperski T, Montelione GT (2004) Backbone 1H, 15N and 13C assignments for the 21 kDa Caenorhabditis elegans homologue of “brain-specific” protein. J Biomol NMR 28:91–92PubMedCrossRefGoogle Scholar
  28. 28.
    Kobayashi N, Koshiba S, Inoue M, Kigawa T, Yokoyama S (2005) Solution structure of mouse CGI-38 protein. http://www.pdb.org/pdb/explore/explore.do?structureId=1WLM
  29. 29.
    Jones DT. (1999) Protein secondary structure prediction based on position-specific scoring matrices. J Mol Biol 292:195–202PubMedCrossRefGoogle Scholar
  30. 30.
    Bryson K, McGuffin LJ, Marsden RL, Ward JJ, Sodhi JS, Jones DT (2005) Protein structure prediction servers at University College London. Nucl Acids Res 33:W36–38PubMedCrossRefGoogle Scholar
  31. 31.
    Hlavanda E, Klement E, Kókai E, Vincze O, Tőkési N, Orosz F, Medzihradszky KF, Dombrádi V, Ovádi J (2007) Phosphorylation blocks the activity of tubulin polymerization-promoting protein (TPPP) – Identification of sites targeted by different kinases. J Biol Chem 282:29531–29539PubMedCrossRefGoogle Scholar
  32. 32.
    Lehotzky A, Tirián L, Tőkési N, Lénárt P, Szabó B, Kovács J, Ovádi J (2004) Dynamic targeting of microtubules by TPPP/p25 affects cell survival. J Cell Sci 117:6249–6259PubMedCrossRefGoogle Scholar
  33. 33.
    Martin CP, Vazquez J, Avila J, Moreno FJ (2002) P24, a glycogen synthase kinase 3 (GSK 3) inhibitor. Biochim Biophys Acta-Mol Basis Dis 1586:113–122Google Scholar
  34. 34.
    Yokozeki T, Homma K, Kuroda S, Kikkawa U, Ohno S, Takahashi M, Imahori K, Kanaho Y (1998) Phosphatidic acid-dependent phosphorylation of a 29-kDa protein by protein kinase C alpha in bovine brain cytosol. J Neurochem 71:410–417PubMedCrossRefGoogle Scholar
  35. 35.
    Acevedo K, Li R, Soo P, Suryadinata R, Sarcevic B, Valova VA, Graham ME, Robinson PJ, Bernard O (2007) The phosphorylation of p25/TPPP by LIM kinase 1 inhibits its ability to assemble microtubules. Exp Cell Res 313:4091–4106PubMedCrossRefGoogle Scholar
  36. 36.
    Kleinnijenhuis AJ, Hedegaard C, Lundvig D, Sundbye S, Issinger OG, Jensen ON, Jensen PH (2008) Identification of multiple post-translational modifications in the porcine brain specific p25alpha. J Neurochem 106:925–933PubMedCrossRefGoogle Scholar
  37. 37.
    Song YJC, Lundvig DMS, Huang Y, Gai WP, Blumbergs PC, Hojrup P, Otzen D, Halliday GM, Jensen PH (2007) P25 alpha relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy. Am J Pathol 171:1291–1303PubMedCrossRefGoogle Scholar
  38. 38.
    Lehotzky A, Tőkési N, Gonzalez-Alvarez I, Merino V, Bermejo M, Orosz F, Lau P, Kovacs GG, Ovádi J (2008) Progress in the development of early diagnosis and a drug with unique pharmacology to improve cancer therapy. Philos Transact A Math Phys Eng Sci 366:3599–3617PubMedCrossRefGoogle Scholar
  39. 39.
    Skjoerringe T, Lundvig DMS, Jensen PH, Moos T (2006) P25 alpha/tubulin polymerization promoting protein expression by myelinating oligodendrocytes of the developing rat brain. J Neurochem 99:333–342PubMedCrossRefGoogle Scholar
  40. 40.
    Lindersson E, Lundvig D, Petersen C, Madsen P, Nyengaard JR, Hojrup P, Moos T, Otzen D, Gai WP, Blumbergs PC, Jensen PH (2005) p25alpha Stimulates alpha-synuclein aggregation and is co-localized with aggregated alpha-synuclein in alpha-synucleinopathies. J Biol Chem 280:5703–5715PubMedCrossRefGoogle Scholar
  41. 41.
    Tsuchiya K, Tajima H, Kuwae T, Takeshima T, Nakano T, Tanaka M, Sunaga K, Fukuhara Y, Nakashima K, Ohama E, Mochizuki H, Mizuno Y, Katsube N, Ishitani R (2005) Pro-apoptotic protein glyceraldehyde-3-phosphate dehydrogenase promotes the formation of Lewy body-like inclusions. Eur J Neurosci 21:317–326PubMedCrossRefGoogle Scholar
  42. 42.
    Ovádi J, Orosz F, Hollán S (2004) Functional aspects of cellular microcompartmentation in the development of neurodegeneration: mutation induced aberrant protein-protein associations. Mol Cell Biochem 256–257:83–93PubMedCrossRefGoogle Scholar
  43. 43.
    Sirover MA (2005) New nuclear functions of the glycolytic protein, glyceraldehyde-3-phosphate dehydrogenase, in mammalian cells. J Cell Biochem 95:45–52PubMedCrossRefGoogle Scholar
  44. 44.
    Sirover MA (1999) New insights into an old protein: the functional diversity of mammalian glyceraldehyde-3-phosphate dehydrogenase. Biochim Biophys Acta 1432:159–184Google Scholar
  45. 45.
    Oláh J, Tőkési N, Vincze O, Horváth I, Lehotzky A, Erdei A, Szájli E, Katalin FM, Orosz F, Kovács GG et al. (2006) Interaction of TPPP/p25 protein with glyceraldehyde-3-phosphate dehydrogenase and their co-localization in Lewy bodies. FEBS Lett 580:5807–5814Google Scholar
  46. 46.
    Jordan BA, Fernholz BD, Boussac M, Xu C, Grigorean G, Ziff EB, Neubert TA (2004) Identification and verification of novel rodent postsynaptic density proteins. Mol Cell Proteomics 3:857–871Google Scholar
  47. 47.
    Li KW, Hornshaw MP, Van der Schors RC, Watson R, Tate S, Casetta B, Jimenez CR, Gouwenberg Y, Gundelfinger ED, Smalla KH et al. (2004) Proteomics analysis of rat brain postsynaptic density. Implications of the diverse protein functional groups for the integration of synaptic physiology. J Biol Chem 279:987–1002Google Scholar
  48. 48.
    Yoshimura Y, Yamauchi Y, Shinkawa T, Taoka M, Donai H, Takahashi N, Isobe T, Yamauchi T (2004) Molecular constituents of the postsynaptic density fraction revealed by proteomic analysis using multidimensional liquid chromatography–tandem mass spectrometry. J Neurochem 88:759–768Google Scholar
  49. 49.
    Collins MO, Yu L, Coba MP, Husi H, Campuzano I, Blackstock WP, Choudhary JS, Grant SG (2005) Proteomic analysis of in vivo phosphorylated synaptic proteins. J Biol Chem 280:5972–5982PubMedCrossRefGoogle Scholar
  50. 50.
    Nelson TJ, Backlund PS, Alkon DL (2004) Hippocampal protein-protein interactions in spatial memory. Hippocampus 14:46–57PubMedCrossRefGoogle Scholar
  51. 51.
    Lee VM, Trojanowski JQ (2006) Mechanisms of Parkinson’s disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron 53:33–38CrossRefGoogle Scholar
  52. 52.
    Ovádi J, Orosz F (2007) Energy metabolism in conformational diseases. In: Bertau M, Mosekilde E, Westerhoff H (eds.) Biosimulation in drug development. Wiley-VCH, Weinheim, Germany. pp. 233–257CrossRefGoogle Scholar
  53. 53.
    DeGiorgis JA, Jaffe H, Moreira JE, Carlotti CG, Leite JP, Pant HC, Dosemeci A (2005) Phosphoproteomic analysis of synaptosomes from human cerebral cortex. J Proteome Res 4:306–315PubMedCrossRefGoogle Scholar
  54. 54.
    Trinidad JC, Specht CG, Thalhammer A, Schoepfer R, Burlingame AL (2006) Comprehensive identification of phosphorylation sites in postsynaptic density preparations.Mol Cell Proteomics 5:914–922PubMedCrossRefGoogle Scholar
  55. 55.
    Iijima T, Mishima T, Akagawa K, Iwao Y (2003) Mitochondrial hyperpolarization after transient oxygen-glucose deprivation and subsequent apoptosis in cultured rat hippocampal neurons. Brain Res 993:140–145PubMedCrossRefGoogle Scholar
  56. 56.
    Collins TJ, Bootman MD (2003) Mitochondria are morphologically heterogeneous within cells. J Exp Biol 206:1993–2000PubMedCrossRefGoogle Scholar
  57. 57.
    Louis JC, Magal E, Muir D, Manthorpe M, Varon S (1992). CG-4, a new bipotential glial cell line from rat brain, is capable of differentiating in vitro into either mature oligodendrocytes or type-2 astrocytes. J Neurosci Res 31:193–204PubMedCrossRefGoogle Scholar
  58. 58.
    Harauz G, Ishiyama N, Hill CM, Bates IR, Libich DS, Farès C. (2004) Myelin basic protein-diverse conformational states of an intrinsically unstructured protein and its roles in myelin assembly and multiple sclerosis. Micron 35:503–542PubMedCrossRefGoogle Scholar
  59. 59.
    Dugas JC, Tai YC, Speed TP, Ngai J, Barres BA (2006) Functional genomic analysis of oligodendrocyte differentiation. J Neurosci 26:10967–10983PubMedCrossRefGoogle Scholar
  60. 60.
    Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL, Krieg PA, Krupenko SA et al. (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28:264–278PubMedCrossRefGoogle Scholar
  61. 61.
    Agresti C, Meomartini ME, Amadio S, Ambrosini E, Volonté C, Aloisi F, Visentin S (2005) ATP regulates oligodendrocyte progenitor migration, proliferation, and differentiation: involvement of metabotropic P2 receptors. Brain Res Brain Res Rev 48:157–165.PubMedCrossRefGoogle Scholar
  62. 62.
    Olanow CW, Perl DP, DeMartino GN, McNaught KS (2004) Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol 3:496–503.PubMedCrossRefGoogle Scholar
  63. 63.
    Johnston JA, Ward CL, Kopito RR (1998) Aggresomes: A cellular response to misfolded proteins. J Cell Biol 143:1883–1898PubMedCrossRefGoogle Scholar
  64. 64.
    Takahashi M, Tomizawa K, Fujita SC, Sato K, Uchida T, Imahori K (1993) A brain-specific protein p25 is localized and associated with oligodendrocytes, neuropil, and fiber-like structures of the CA hippocampal region in the rat brain. J Neurochem 60:228–235PubMedCrossRefGoogle Scholar
  65. 65.
    Kovacs GG, Gelpi E, Lehotzky A, Hoftberger R, Erdei A, Budka H, Ovádi J (2007) The brain-specific protein TPPP/p25 in pathological protein deposits of neurodegenerative diseases. Acta Neuropathol 113:153–161PubMedCrossRefGoogle Scholar
  66. 66.
    Akiyama K, Ichinose S, Omori A, Sakurai Y, Asou H (2002). Study of expression of myelin basic proteins (MBPs) in developing rat brain using a novel antibody reacting with four major isoforms of MBP. J Neurosci Res 68:19–28PubMedCrossRefGoogle Scholar
  67. 67.
    Colello RJ, Fuss B, Fox MA, Alberti J (2002) A proteomic approach to rapidly elucidate oligodendrocyte-associated proteins expressed in the myelinating rat optic nerve. Electrophoresis 23:144–151.PubMedCrossRefGoogle Scholar
  68. 68.
    Preusser M, Lehotzky A, Budka H, Ovádi J, Kovacs GG (2007) TPPP/p25 in brain tumours: expression in non-neoplastic oligodendrocytes but not in oligodendroglioma cells. Acta Neuropathol 113:213–215PubMedCrossRefGoogle Scholar
  69. 69.
    Tribl F, Marcus K, Meyer HE, Bringmann G, Gerlach M, Riederer P (2006) Subcellular proteomics reveals neuromelanin granules to be a lysosome-related organelle. J Neural Transm 113:741–749PubMedCrossRefGoogle Scholar
  70. 70.
    Tribl F, Gerlach M, Marcus K, Asan E, Tatschner T, Arzberger T, Meyer HE, Bringmann G, Riederer P (2005) “Subcellular proteomics” of neuromelanin granules isolated from the human brain. Mol Cell Proteomics 4:945–957PubMedCrossRefGoogle Scholar
  71. 71.
    Takamori S, Holt M, Stenius K, Lemke EA, Grønborg M, Riedel D, Urlaub H, Schenck S, Brügger B, Ringler P et al. (2006) Molecular anatomy of a trafficking organelle. Cell 127:831–846PubMedCrossRefGoogle Scholar
  72. 72.
    Blondeau F, Ritter B, Allaire PD, Wasiak S, Girard M, Hussain NK, Angers A, Legendre-Guillemin V, Roy L, Boismenu D et al. (2004) Tandem MS analysis of brain clathrin-coated vesicles reveals their critical involvement in synaptic vesicle recycling. Proc. Natl Acad Sci. USA 101:3833–3838PubMedCrossRefGoogle Scholar
  73. 73.
    Pabst S, Margittai M, Vainius D, Langen R, Jahn R, Fasshauer D (2002) Rapid and selective binding to the synaptic SNARE complex suggests a modulatory role of complexins in neuroexocytosis. J Biol Chem 277:7838–7848PubMedCrossRefGoogle Scholar
  74. 74.
    Vosseller K, Trinidad JC, Chalkley R.J, Specht CG, Thalhammer A, Lynn A.J, Snedecor JO, Guan S, Medzihradszky KF, Maltby DA et al. (2006) O-linked N-acetylglucosamine proteomics of postsynaptic density preparations using lectin weak affinity chromatography and mass spectrometry Mol Cell Proteomics 5:923–934Google Scholar
  75. 75.
    Lyck L, Dalmau I, Chemnitz J, Finsen B, Schrøder HD (2008) Immunohistochemical markers for quantitative studies of neurons and glia in human neocortex. J Histochem Cytochem 56:201–221PubMedCrossRefGoogle Scholar
  76. 76.
    Baker KG, Huang Y, McCann H, Gai WP, Jensen PH, Halliday GM (2006) P25alpha immunoreactive but alpha-synuclein immunonegative neuronal inclusions in multiple system atrophy. Acta Neuropathol 111:193–195PubMedCrossRefGoogle Scholar
  77. 77.
    Jellinger KA (2006) P25alpha immunoreactivity in multiple system atrophy and Parkinson disease. Acta Neuropathol 112:112PubMedCrossRefGoogle Scholar
  78. 78.
    Liu Q, Tan G, Levenkova N, Li T, Pugh EN Jr, Rux JJ, Speicher DW, Pierce EA (2007) The proteome of the mouse photoreceptor sensory cilium complex Mol Cell Proteomics 6:1299–1317PubMedCrossRefGoogle Scholar
  79. 79.
    Mattson MP (1995) Degenerative and protective signaling mechanisms in the neurofibrillary pathology of AD. Neurobiol Aging 16:447–457PubMedCrossRefGoogle Scholar
  80. 80.
    Hutton M, Lewis J, Dickson D, Yen SH, McGowan E (2001) Analysis of tauopathies with transgenic mice. Trends Mol Med 7:467–470PubMedCrossRefGoogle Scholar
  81. 81.
    Yu S, Uéda K, Chan P (2005) Alpha-synuclein and dopamine metabolism. Mol Neurobiol 31:243–254PubMedCrossRefGoogle Scholar
  82. 82.
    Mattson MP (2006) Neuronal life-and-death signaling, apoptosis, and neurodegenerative disorders. Antioxid Redox Signal. 8:1997–2006PubMedCrossRefGoogle Scholar
  83. 83.
    Winklhofer KF, Tatzelt J (2006) The role of chaperones in Parkinson’s disease and prion diseases. Handb Exp Pharmacol 172:221–258PubMedCrossRefGoogle Scholar
  84. 84.
    Agorogiannis EI, Agorogiannis GI, Papadimitriou A, Hadjigeorgiou GM (2004) Protein misfolding in neurodegenerative diseases. Neuropathol Appl Neurobiol 30:215–224PubMedCrossRefGoogle Scholar
  85. 85.
    Lee HG, Perry G, Moreira PI, Garrett MR, Liu Q, Zhu X, Takeda A, Nunomura A, Smith MA (2005) Tau phosphorylation in Alzheimer’s disease: pathogen or protector? Trends Mol Med 11:164–169PubMedCrossRefGoogle Scholar
  86. 86.
    Scheibel T, Buchner J (2006) Protein aggregation as a cause for disease. Handb Exp Pharmacol 172:199–219PubMedCrossRefGoogle Scholar
  87. 87.
    Hol EM, Scheper W (2008) Protein quality control in neurodegeneration: walking the tight rope between health and disease. J Mol Neurosci. 34:23–33Google Scholar
  88. 88.
    Tanaka M, Kim YM, Lee G, Junn E, Iwatsubo T, Mouradian MM (2004) Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. J Biol Chem 279:4625–4631PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Ferenc Orosz
    • 1
  • Attila Lehotzky
  • Judit Oláh
  • Judit Ovádi
  1. 1.Institute of EnzymologyBiological Research Center, Hungarian Academy of SciencesBudapestHungary

Personalised recommendations