Skip to main content
SpringerLink
Log in

Novel Proteins in α-Synucleinopathies

  • Chapter
Protein Folding and Misfolding: Neurodegenerative Diseases

Part of the book series: Focus on Structural Biology ((FOSB,volume 7))

  • 1124 Accesses

Abstract

α-Synucleinopathies are a group of neurodegenerative disorders characterized by the presence of intracytoplasmic Lewy bodies in Parkinson’s disease and dementia with Lewy bodies as well as glial cytoplasmic inclusions in multiple system atrophy. The main component of these inclusions is aggregated α-synuclein which supports a strong link between α-synuclein and disease pathogenesis. The mechanisms responsible for α-synuclein aggregation and subsequent degeneration are largely unknown. However, several factors have been shown to accelerate the aggregation of α-synuclein in vitro and suggested to contribute to the pathogenesis of α-synucleinopathies. Several different proteins can stimulate the aggregation process in vitro and have been shown to colocalize with aggregated α-synuclein in pathological brain tissue. We review our current knowledge on proteins with a putative involvement in α-synuclein-dependent degeneration based on aggregatory properties, colocalization with aggregated α-synuclein, or genetic evidence.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Arima K, Ueda K, Sunohara N, Hirai S, Izumiyama Y, Tonozuka-Uehara H, Kawai M (1998) Immunoelectron-microscopic demonstration of NACP/alpha-synuclein- epitopes on the filamentous component of Lewy bodies in Parkinson’s disease and in dementia with Lewy bodies. Brain Res 808:93–100

    PubMed  CAS  Google Scholar 

  2. Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM, Trojanowski JQ, Iwatsubo T (1998) Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 152:879–884

    PubMed  CAS  Google Scholar 

  3. Crowther RA, Jakes R, Spillantini MG, Goedert M (1998) Synthetic filaments assembled from C-terminally truncated alpha-synuclein. FEBS Lett 436:309–312

    PubMed  CAS  Google Scholar 

  4. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840

    PubMed  CAS  Google Scholar 

  5. Gai WP, Power JHT, Blumbergs PC, Blessing WW (1998) Multiple-system atrophy: a new alpha-synuclein disease? Lancet 352:547–548

    PubMed  CAS  Google Scholar 

  6. Gai WP, Pountney DL, Power JHT, Li QX, Culvenor JG, Mclean CA, Jensen PH, Blumbergs PC (2003) alpha-Synuclein fibrils constitute the central core of oligodendroglial inclusion filaments in multiple system atrophy. Exp Neurol 181:68–78

    PubMed  CAS  Google Scholar 

  7. Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M (1998) Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 251:205–208

    PubMed  CAS  Google Scholar 

  8. Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H (1998) alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249:180–182

    PubMed  CAS  Google Scholar 

  9. Arawaka S, Saito Y, Murayama S, Mori H (1998) Lewy body in neurodegeneration with brain iron accumulation type 1 is immunoreactive for alpha-synuclein. Neurology 51:887–889

    PubMed  CAS  Google Scholar 

  10. Marti MJ, Tolosa E, Campdelacreu J (2003) Clinical overview of the synucleinopathies. Mov Disorders 18:S21–S27

    Google Scholar 

  11. Goedert M, Spillantini MG, Davies SW (1998) Filamentous nerve cell inclusions in neurodegenerative diseases. Curr Opin Neurobiol 8:619–632

    PubMed  CAS  Google Scholar 

  12. Spillantini MG, Goedert M (2000) The alpha-synucleinopathies: Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Ann N Y Acad Sci 920:16–27

    PubMed  CAS  Google Scholar 

  13. Trojanowski JQ, Lee VMY (2002) Parkinson’s disease and related alpha-synucleinopathies a new class of nervous system amyloidoses. Neurotox 20:457–460

    Google Scholar 

  14. Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108

    PubMed  CAS  Google Scholar 

  15. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047

    PubMed  CAS  Google Scholar 

  16. Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B et al. (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173

    PubMed  CAS  Google Scholar 

  17. Farrer M, Kachergus J, Forno L, Lincoln S, Wang DS, Hulihan M, Maraganore D, Gwinn-Hardy K, Wszolek Z, Dickson D et al. (2004) Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol 55:174–179

    PubMed  CAS  Google Scholar 

  18. Singleton AB, 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

    PubMed  CAS  Google Scholar 

  19. Gai WP, Power JH, Blumbergs PC, Culvenor JG, Jensen PH (1999) Alpha-synuclein immunoisolation of glial inclusions from multiple system atrophy brain tissue reveals multiprotein components. J Neurochem 73:2093–2100

    PubMed  CAS  Google Scholar 

  20. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc Natl Acad Sci USA 95:6469–6473

    PubMed  CAS  Google Scholar 

  21. Conway KA, Lee SJ, Rochet JC, Ding TT, Harper JD, Williamson RE, Lansbury PT Jr. (2000) Accelerated oligomerization by Parkinson’s disease linked alpha-synuclein mutants. Ann N Y Acad Sci 920:42–45

    PubMed  CAS  Google Scholar 

  22. Greenbaum EA, Graves CL, Mishizen-Eberz AJ, Lupoli MA, Lynch DR, Englander SW, Axelsen PH, Giasson BI (2005) The E46K mutation in alpha-synuclein increases amyloid fibril formation. J Biol Chem 280:7800–7807

    PubMed  CAS  Google Scholar 

  23. Narhi L, Wood SJ, Steavenson S, Jiang Y, Wu GM, Anafi D, Kaufman SA, Martin F, Sitney K, Denis P et al. (1999) Both familial Parkinson’s disease mutations accelerate alpha-synuclein aggregation. J Biol Chem 274:9843–9846

    PubMed  CAS  Google Scholar 

  24. Galpern WR, Lang AE (2006) Interface between tauopathies and synucleinopathies: a tale of two proteins. Ann Neurol 59:449–458

    PubMed  CAS  Google Scholar 

  25. Chen L, Feany MB (2005) alpha-Synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci 8: 657–663

    PubMed  CAS  Google Scholar 

  26. Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T (2002) alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164

    PubMed  CAS  Google Scholar 

  27. Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, Masliah E (1999) Oxidative stress induces amyloid-like aggregate formation of NACP/alpha- synuclein in vitro. Neuroreport 10:717–721

    PubMed  CAS  Google Scholar 

  28. McNaught KS, Olanow CW, Halliwell B, Isacson O, Jenner P (2001) Failure of the ubiquitin-proteasome system in Parkinson’s disease. Nat Rev Neurosci 2:589–594

    PubMed  CAS  Google Scholar 

  29. Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Rev 33: 95–130

    PubMed  CAS  Google Scholar 

  30. Lindersson E, Lundvig D, Petersen C, Madsen P, Nyengaard JR, Hojrup P, Moos T, Otzen D, Gai WP, Blumbergs PC et al. (2005) p25alpha Stimulates alpha-synuclein aggregation and is co-localized with aggregated alpha-synuclein in alpha-synucleinopathies. J Biol Chem 280:5703–5715

    PubMed  CAS  Google Scholar 

  31. Liu IH, Uversky VN, Munishkina LA, Fink AL, Halfter W, Cole GJ (2005) Agrin binds alpha-synuclein and modulates alpha-synuclein fibrillation. Glycobiology 15:1320–1331

    PubMed  CAS  Google Scholar 

  32. Takeda A, Arai N, Komori T, Iseki E, Kato S, Oda M (1997) Tau immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 234:63–66

    PubMed  CAS  Google Scholar 

  33. Braak H, Braak E (2000) Pathoanatomy of Parkinson’s disease. J Neurol 247 Suppl 2:II 3–10

    Google Scholar 

  34. Forno LS (1996) Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 55: 259–272

    PubMed  CAS  Google Scholar 

  35. Braak H, Del Tredici K, Rub U, De Vos RAI, Steur ENHJ, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211

    PubMed  Google Scholar 

  36. Thomas B, Beal MF (2007) Parkinson’s disease. Hum Mol Genet 16:R183–R194

    PubMed  CAS  Google Scholar 

  37. Gasser T (2007) Update on the genetics of Parkinson’s disease. Mov Disorders 22: S343–S350

    Google Scholar 

  38. Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M, de Munain AL, Aparicio S, Gil AM, Khan N et al. (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44:595–600

    PubMed  CAS  Google Scholar 

  39. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB et al. (2004) Mutations in LRRK2 cause autosomal-dominant Parkinsonism with pleomorphic pathology. Neuron 44:601–607

    PubMed  CAS  Google Scholar 

  40. Hohl U, CoreyBloom J, Hansen LA, Thomas RG, Thal LJ (1997) Diagnostic accuracy of dementia with Lewy bodies: A prospective evaluation. Neurology 48:2032

    Google Scholar 

  41. Hansen LA, Samuel W (1997) Criteria for Alzheimer’s disease and the nosology of dementia with Lewy bodies. Neurology 48:126–132

    PubMed  CAS  Google Scholar 

  42. Burn DJ, Jaros E (2001) Multiple system atrophy: cellular and molecular pathology. J Clin Pathol Mol Pathol 54:419–426

    CAS  Google Scholar 

  43. Jellinger KA (2003) Neuropathological spectrum of synucleinopathies. Mov Disorders 18:S2–S12

    Google Scholar 

  44. Wakabayashi K, Takahashi H (2006) Cellular pathology in multiple system atrophy. Neuropathol 26:338–345

    Google Scholar 

  45. Nishie M, Mori F, Yoshimoto M, Takahashi H, Wakabayashi K (2004) A quantitative investigation of neuronal cytoplasmic and intranuclear inclusions in the pontine and inferior olivary nuclei in multiple system atrophy. Neuropathol App Neurobiol 30:546–554

    CAS  Google Scholar 

  46. Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein – A neuron-specific protein localized to the nucleus and presynaptic nerve-terminal. J Neurosci 8:2804–2815

    PubMed  CAS  Google Scholar 

  47. Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM, Armanini M, Ryan A et al. (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252

    PubMed  CAS  Google Scholar 

  48. Clayton DF, George JM (1998) The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci 21:249–254

    PubMed  CAS  Google Scholar 

  49. Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT Jr. (1996) NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochem 35: 13709–13715

    CAS  Google Scholar 

  50. Giasson BI, Uryu K, Trojanowski JQ, Lee VM (1999) Mutant and wild type human alpha-synucleins assemble into elongated filaments with distinct morphologies in vitro. J Biol Chem 274:7619–7622

    PubMed  CAS  Google Scholar 

  51. Hashimoto M, Hsu LJ, Sisk A, Xia Y, Takeda A, Sundsmo M, Masliah E (1998) Human recombinant NACP/alpha-synuclein is aggregated and fibrillated in vitro: relevance for Lewy body disease. Brain Res 799:301–306

    PubMed  CAS  Google Scholar 

  52. Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, Lansbury PT, Jr. (2000) Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson’s disease: implications for pathogenesis and therapy. Proc Natl Acad Sci USA 97:571–576

    PubMed  CAS  Google Scholar 

  53. Lashuel H, Petre B, Wall J, Simon M, Nowak R, Walz T, Lansbury P (2002) alpha-Synuclein, especially the Parkinson’s disease-associated mutants, forms pore-like annular and tubular protofibrils. J Mol Biol 322:1089

    PubMed  CAS  Google Scholar 

  54. Uversky VN (2007) Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. J Neurochem 103:17–37

    PubMed  CAS  Google Scholar 

  55. Volles MJ, Lansbury PT Jr. (2002) Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson’s disease-linked mutations and occurs by a pore-like mechanism. Biochem 41:4595–4602

    CAS  Google Scholar 

  56. Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, Caccavello RJ, Barbour R, Huang JP, Kling K, Lee M et al. (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281:29739–29752

    PubMed  CAS  Google Scholar 

  57. Nishie M, Mori F, Fujiwara H, Hasegawa M, Yoshimoto M, Iwatsubo T, Takahashi H, Wakabayashi K (2004) Accumulation of phosphorylated alpha-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy. Acta Neuropathol 107: 292–298

    PubMed  CAS  Google Scholar 

  58. Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, Lee VM (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985–989

    PubMed  CAS  Google Scholar 

  59. Souza JM, Giasson BI, Chen QP, Lee VMY, Ischiropoulos H (2000) Dityrosine cross-linking promotes formation of stable alpha-synuclein polymers – Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J Biol Chem 275:18344–18349

    PubMed  CAS  Google Scholar 

  60. Conway KA, Rochet JC, Bieganski RM, Lansbury PT, Jr. (2001) Kinetic stabilization of the alpha-synuclein protofibril by a dopamine – alpha-synuclein adduct. Science 294: 1346–1349

    PubMed  CAS  Google Scholar 

  61. Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VMY (2003) Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 300:636–640

    PubMed  CAS  Google Scholar 

  62. Dev KK, Hofele K, Barbieri S, Buchman VL, van der Putten H (2003) Part II: alpha-synuclein and its molecular pathophysiological role in neurodegenerative disease. Neuropharmacology 45:14–44

    PubMed  CAS  Google Scholar 

  63. 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 289:37–43

    PubMed  CAS  Google Scholar 

  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$_3$ hippocampal region in the rat-brain. J Neurochem 60:228–235

    PubMed  CAS  Google Scholar 

  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 113:153–161

    PubMed  CAS  Google Scholar 

  66. 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 171:1291–1303

    PubMed  CAS  Google Scholar 

  67. 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 99:333–342

    PubMed  CAS  Google Scholar 

  68. 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 14:1396–1409

    CAS  Google Scholar 

  69. 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 44:121–122

    PubMed  CAS  Google Scholar 

  70. 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 47:266–268

    PubMed  CAS  Google Scholar 

  71. 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. Biochem 41:8657–8664

    CAS  Google Scholar 

  72. Lehotzky A, Tirián L, Tökési N, Lénárt P, Szabó B, Kovács J, Ovádi J (2004) Dynamic targeting of microtubules by TPPP/p25 affects cell survival. J Cell Sci 117:6249–6259

    PubMed  CAS  Google Scholar 

  73. 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 100:13976–13981.

    PubMed  Google Scholar 

  74. Sirover MA (2005) New nuclear functions of the glycolytic protein, glyceraldehyde-3-phosphate dehydrogenase, in mammalian cells. J Cell Biochem 95:45–52

    PubMed  CAS  Google Scholar 

  75. Chuang DM, Hough C, Senatorov VV (2005) Glyceraldehyde-3-phosphate dehydrogenase, apoptosis and neurodegenerative diseases. Annu Rev Pharmacol Toxicol 45:269–290

    PubMed  CAS  Google Scholar 

  76. Oláh J, Tökési N, Vincze O, Horváth I, Lehotzky A, Erdei A, Szájli E, Katalin FM, Orosz F, Kovacs GG et al. (2006) Interaction of TPPP/p25 protein with glyceraldehyde-3-phosphate dehydrogenase and their co-localization in Lewy bodies. FEBS Lett 580:5807–5814

    PubMed  Google Scholar 

  77. Nelson TJ, Backlund PS, Alkon DL (2004) Hippocampal protein-protein interactions in spatial memory. Hippocampus 14:46–57

    PubMed  CAS  Google Scholar 

  78. Mcmahon HT, Missler M, Li C, Sudhof TC (1995) Complexins – Cytosolic Proteins That Regulate Snap Receptor Function. Cell 83:111–119

    PubMed  CAS  Google Scholar 

  79. Hlavanda E, Klement E, Kókai E, Vincze O, Tökési 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 282:29531–29539

    PubMed  CAS  Google Scholar 

  80. Martin CP, Vazquez J, Avila J, Moreno FJ (2002) P24, a glycogen synthase kinase 3 (GSK 3) inhibitor. Biochim Biophys Acta-Mol Basis Dis 1586:113–122

    Google Scholar 

  81. 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 313:4091–4106

    PubMed  CAS  Google Scholar 

  82. 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 71:410–417

    PubMed  CAS  Google Scholar 

  83. Baker KG, Huang Y, McCann H, Gai WP, Jensen PH, Halliday GM (2006) P25 alpha immunoreactive but alpha-synuclein immunonegative neuronal inclusions in multiple system atrophy. Acta Neuropathol 111:193–195

    PubMed  Google Scholar 

  84. Kovacs GG, László L, Kovács J, Jensen PH, Lindersson E, Botond G, Molnár T, Perczel A, Hudecz F, Mezö G et al. (2004) Natively unfolded tubulin polymerization promoting protein TPPP/p25 is a common marker of alpha-synucleinopathies. Neurobiol Dis 17:155–162

    PubMed  CAS  Google Scholar 

  85. Jellinger KA (2006) P25 alpha immunoreactivity in multiple system atrophy and Parkinson disease. Acta Neuropathol 112:112

    PubMed  Google Scholar 

  86. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989) Multiple isoforms of human microtubule-associated protein tau – sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3:519–526

    PubMed  CAS  Google Scholar 

  87. Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA (1989) Cloning and sequencing of the cDNA-encoding an isoform of microtubule-associated protein tau containing 4 tandem repeats: differential expression of tau protein messenger-RNAs in human-brain. EMBO J 8:393–399

    PubMed  CAS  Google Scholar 

  88. Forman MS, Lee VMY, Trojanowski JQ (2000) New insights into genetic and molecular mechanisms of brain degeneration in tauopathies. J Chem Neuroanat 20:225–244

    PubMed  CAS  Google Scholar 

  89. Litvan I (2003) Update on epidemiological aspects of progressive supranuclear palsy. Mov Disorders 18:S43–S50

    Google Scholar 

  90. Dickson DW, Bergeron C, Chin SS, Duyckaerts C, Horoupian D, Ikeda K, Jellinger K, Lantos PL, Lippa CF, Mirra SS et al. (2002) Office of rare diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 61:935–946

    PubMed  CAS  Google Scholar 

  91. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A et al. (1998) Association of missense and $5′$-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705

    PubMed  CAS  Google Scholar 

  92. Giasson BI, Lee VMY, Trojanowski JQ (2003) Interactions of amyloidogenic proteins. Neuromol Med 4:49–58

    CAS  Google Scholar 

  93. Conway KA, Harper JD, Lansbury PT (1998) Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat Med 4:1318–1320

    PubMed  CAS  Google Scholar 

  94. Goedert M, Jakes R, Spillantini MG, Hasegawa M, Smith MJ, Crowther RA (1996) Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383:550–553

    PubMed  CAS  Google Scholar 

  95. Horiguchi T, Uryu K, Giasson BI, Ischiropoulos H, LightFoot R, Bellmann C, Richter-Landsberg C, Lee VMY, Trojanowski JQ (2003) Nitration of tau protein is linked to neurodegeneration in tauopathies. Am J Pathol 163:1021–1031

    PubMed  CAS  Google Scholar 

  96. Hasegawa M, Fujiwara H, Nonaka T, Wakabayashi K, Takahashi H, Lee VMY, Trojanowski JQ, Mann D, Iwatsubo T (2002) Phosphorylated alpha-synuclein is ubiquitinated in alpha-synucleinopathy lesions. J Biol Chem 277:49071–49076

    PubMed  CAS  Google Scholar 

  97. Lee VMY, Giasson BI, Trojanowski JQ (2004) More than just two peas in a pod: common amyloidogenic properties of tau and alpha-synuclein in neurodegenerative diseases. Trends Neurosci 27:129–134

    PubMed  CAS  Google Scholar 

  98. Engelender S, Kaminsky Z, Guo X, Sharp AH, Amaravi RK, Kleiderlein JJ, Margolis RL, Troncoso JC, Lanahan AA, Worley PF et al. (1999) Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nat Genet 22:110–114

    PubMed  CAS  Google Scholar 

  99. Kawamata H, Mclean PJ, Sharma N, Hyman BT (2001) Interaction of alpha-synuclein and synphilin-1: effect of Parkinson’s disease-associated mutations. J Neurochem 77:929–934

    PubMed  CAS  Google Scholar 

  100. Engelender S, Wakabayashi K, Wanner T, Kaminsky Z, Kleiderlein JJ, Margolis RL, Tsuji S, Takahashi H, Ross CA (1999) The alpha-synuclein-associated protein, synphilin-1: Gene structure and localization, and presence of synphilin-1 protein in Lewy bodies. Am J Hum Genet 65:A270

    Google Scholar 

  101. Ribeiro CS, Carneiro K, Ross CA, Menezes JRL, Engelender S (2002) Synphilin-1 is developmentally localized to synaptic terminals, and its association with synaptic vesicles is modulated by alpha-synuclein. J Biol Chem 277:23927–23933

    PubMed  CAS  Google Scholar 

  102. Smith WW, Margolis RL, Li XJ, Troncoso JC, Lee MK, Dawson VL, Dawson TM, Iwatsubo T, Ross CA (2005) alpha-Synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. J Neurosci 25:5544–5552

    PubMed  CAS  Google Scholar 

  103. Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM (2001) Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med 7:1144–1150

    PubMed  CAS  Google Scholar 

  104. Ito T, Niwa J, Hishikawa N, Ishigaki S, Doyu M, Sobue G (2003) Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1. J Biol Chem 278:29106–29114

    PubMed  CAS  Google Scholar 

  105. Nagano Y, Yamashita H, Takahashi T, Kishida S, Nakamura T, Iseki E, Hattori N, Mizuno Y, Kikuchi A, Matsumoto M (2003) Siah-1 facilitates ubiquitination and degradation of synphilin-1. J Biol Chem 278:51504–51514

    PubMed  CAS  Google Scholar 

  106. Liani E, Eyal A, Avraham E, Shemer R, Szargel R, Berg D, Bornemann A, Riess O, Ross CA, Rott R et al. (2004) Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson’s disease. Proc Natl Acad Sci USA 101:5500–5505

    PubMed  CAS  Google Scholar 

  107. Wakabayashi K, Engelender S, Yoshimoto M, Tsuji S, Ross CA, Takahashi H (2000) Synphilin-1 is present in Lewy bodies in Parkinson’s disease. Ann Neurol 47:521–523

    PubMed  CAS  Google Scholar 

  108. Wakabayashi K, Engelender S, Tanaka Y, Yoshimoto M, Mori F, Tsuji S, Ross CA, Takahashi H (2002) Immunocytochemical localization of synphilin-1, an alpha-synuclein-associated protein, in neurodegenerative disorders. Acta Neuropathol 103:209–214

    PubMed  CAS  Google Scholar 

  109. Eyal A, Szargel R, Avraham E, Liani E, Haskin J, Rott R, Engelender S: Synphilin-1A (2006) An aggregation-prone isoform of synphilin-1 that causes neuronal death and is present in aggregates from alpha-synucleinopathy patients. Proc Natl Acad Sci USA 103: 5917–5922

    PubMed  CAS  Google Scholar 

  110. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM et al. (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133

    PubMed  CAS  Google Scholar 

  111. Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, Dara R, Graff-Radford NR, Hutton ML, Dickson DW (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445

    PubMed  CAS  Google Scholar 

  112. Higashi S, Iseki E, Yamamoto R, Minegishi M, Hino H, Fujisawa K, Togo T, Katsuse O, Uchikado H, Furukawa Y et al. (2007) Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res 1184:284–294

    PubMed  CAS  Google Scholar 

  113. MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A (2006) The familial parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52:587–593

    PubMed  CAS  Google Scholar 

  114. Perry G, Zhu X, Babar AK, Siedlak SL, Yang Q, Ito G, Iwatsubo T, Smith MA, Chen SG (2008) Leucine-rich repeat kinase 2 colocalizes with alpha-synuclein in parkinson’s disease, but not tau-containing deposits in tauopathies. Neurodegener Dis 5, 222–224

    PubMed  CAS  Google Scholar 

  115. Gerard M, Debyser Z, Kahle PJ, Baekeland V, Engelborghs Y (2006) The aggregation of alpha-synuclein is stimulated by FK506 binding proteins as shown by fluorescence correlation spectroscopy. FASEB J 20:A954

    Google Scholar 

  116. Galat A (2003) Peptidylprolyl cis/trans isomerases (immunophilins): biological diversity – targets – functions. Curr Top Med Chem 3:1315–1347

    PubMed  CAS  Google Scholar 

  117. Lyons WE, George EB, Dawson TM, Steiner JP, Snyder SH (1994) Immunosuppressant FK506 promotes neurite outgrowth in cultures of PC12 cells and sensory ganglia. Proc Natl Acad Sci USA 91:3191–3195

    PubMed  CAS  Google Scholar 

  118. Gold BG, Katoh K, Stormdickerson T (1995) The immunosuppressant FK506 increases the rate of axonal regeneration in rat sciatic-nerve. J Neurosci 15:7509–7516

    PubMed  CAS  Google Scholar 

  119. Costantini LC, Chaturvedi P, Armistead DM, McCaffrey PG, Deacon TW, Isacson O (1998) A novel immunophilin ligand: distinct branching effects on dopaminergic neurons in culture and neurotrophic actions after oral administration in an animal model of Parkinson’s disease. Exp Neurol 153:382

    Google Scholar 

  120. Avramut M, Achim CL (2002) Immunophilins and their ligands: insights into survival and growth of human neurons. Physiol Behav 77:463–468

    PubMed  CAS  Google Scholar 

  121. Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: Implications for neurodegenerative disorders. Science 287:1265–1269

    PubMed  CAS  Google Scholar 

  122. Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA (2002) The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice – Paraquat and alpha-synuclein. J Biol Chem 277:1641–1644

    PubMed  CAS  Google Scholar 

  123. Goers J, Manning-Bog AB, McCormack AL, Millett IS, Doniach S, Di Monte DA, Uversky VN, Fink AL (2003) Nuclear localization of alpha-synuclein and its interaction with histones. Biochemistry 42:8465–8471

    PubMed  CAS  Google Scholar 

  124. Kontopoulos E, Parvin JD, Feany MB (2006) Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum Mol Genet 15:3012–3023

    PubMed  CAS  Google Scholar 

  125. Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ et al. (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317: 516–519

    PubMed  CAS  Google Scholar 

  126. Lindersson EK, Hojrup P, Gai WP, Locker D, Martin D, Jensen PH (2004) alpha-Synuclein filaments bind the transcriptional regulator HMGB-1. Neuroreport 15:2735–2739

    PubMed  CAS  Google Scholar 

  127. Alim MA, Hossain MS, Arima K, Takeda K, Izumiyama Y, Nakamura M, Kaji H, Shinoda T, Hisanaga S, Ueda K (2002) Tubulin seeds alpha-synuclein fibril formation. J Biol Chem 277:2112–2117

    PubMed  CAS  Google Scholar 

  128. D’Andrea MR, Ilyin S, Plata-Salaman CR (2001) Abnormal patterns of microtubule-associated protein-2 (MAP-2) immunolabeling in neuronal nuclei and Lewy bodies in Parkinson’s disease substantia nigra brain tissues. Neurosci Lett 306:137–140

    PubMed  CAS  Google Scholar 

  129. Jensen PH, Hager H, Nielsen MS, Hojrup P, Gliemann J, Jakes R (1999) alpha-synuclein binds to Tau and stimulates the protein kinase A- catalyzed tau phosphorylation of serine residues 262 and 356. J Biol Chem 274:25481–25489

    PubMed  CAS  Google Scholar 

  130. Jensen PH, Islam K, Kenney J, Nielsen MS, Power J, Gai WP (2000) Microtubule-associated protein 1B is a component of cortical Lewy bodies and binds alpha-synuclein filaments. J Biol Chem 275:21500–21507

    PubMed  CAS  Google Scholar 

  131. Payton JE, Perrin RJ, Clayton DF, George JM (2001) Protein-protein interactions of alpha-synuclein in brain homogenates and transfected cells. Brain Res Mol Brain Res 95:138–145

    PubMed  CAS  Google Scholar 

  132. Sharma N, Hewett J, Ozelius LJ, Ramesh V, McLean PJ, Breakefield XO, Hyman BT (2001) A close association of torsinA and alpha-synuclein in Lewy bodies – A fluorescence resonance energy transfer study. Am J Pathol 159:339–344

    PubMed  CAS  Google Scholar 

  133. Lotharius J, Brundin P (2002) Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson’s disease. Hum Mol Genet 11:2395–2407

    PubMed  CAS  Google Scholar 

  134. Sidhu A, Wersinger C, Vernier P (2004) Does alpha-synuclein modulate dopaminergic synaptic content and tone at the synapse? FASEB J 18:637–647

    Google Scholar 

  135. Donahue JE, Berzin TM, Rafii MS, Glass DJ, Yancopoulos GD, Fallon JR, Stopa EG: Agrin in Alzheimer’s disease (1999) Altered solubility and abnormal distribution within microvasculature and brain parenchyma. J Neuropathol Exp Neurol 58:534

    Google Scholar 

  136. Verbeek MM, Otte-Holler I, van den Born J, van den Heuvel LPWJ, David G, Wesseling P, de Waal RMW (1999) Agrin is a major heparan sulfate proteoglycan accumulating in Alzheimer’s disease brain. Am J Pathol 155:2115–2125

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Medical Biochemistry, University of Aarhus Ole Worms Allé 1.170 DK-8000 Aarhus C, Denmark

    Christine Lund Kragh

Authors
  1. Christine Lund Kragh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Poul Henning Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Hungarian Academy of Sciences, Biological Research Center Institute of Enzymology, Karolina út 29, 1113, Budapest, Hungary

    Judit Ovádi  & Ferenc Orosz  & 

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Kragh, C.L., Jensen, P.H. (2009). Novel Proteins in α-Synucleinopathies. In: Ovádi, J., Orosz, F. (eds) Protein Folding and Misfolding: Neurodegenerative Diseases. Focus on Structural Biology, vol 7. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-9434-7_9

Download citation

Publish with us

Policies and ethics

Search

Navigation