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The Lewy Body in Parkinson’s Disease and Related Neurodegenerative Disorders

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Abstract

The histopathological hallmark of Parkinson’s disease (PD) is the presence of fibrillar aggregates referred to as Lewy bodies (LBs), in which α-synuclein is a major constituent. Pale bodies, the precursors of LBs, may serve the material for that LBs continue to expand. LBs consist of a heterogeneous mixture of more than 90 molecules, including PD-linked gene products (α-synuclein, DJ-1, LRRK2, parkin, and PINK-1), mitochondria-related proteins, and molecules implicated in the ubiquitin–proteasome system, autophagy, and aggresome formation. LB formation has been considered to be a marker for neuronal degeneration because neuronal loss is found in the predilection sites for LBs. However, recent studies have indicated that nonfibrillar α-synuclein is cytotoxic and that fibrillar aggregates of α-synuclein (LBs and pale bodies) may represent a cytoprotective mechanism in PD.

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References

  1. Iwai A, Masliah E, Yoshimoto M et al (1995) The precursor protein of non-Aβ component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 14:467–475

    Article  PubMed  CAS  Google Scholar 

  2. Polymeropoulos MH, Lavedan C, Leroy E et al (1997) Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047

    Article  PubMed  CAS  Google Scholar 

  3. Krüger R, Kuhn W, Muller T et al (1998) Ala30Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nat Genet 18:106–108

    Article  PubMed  Google Scholar 

  4. Zarranz JJ, Alegre J, Gomez-Esteban JC et al (2004) The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173

    Article  PubMed  CAS  Google Scholar 

  5. Singleton AB, Farrer M, Johnson J et al (2003) α-Synuclein locus triplication causes Parkinson’s disease. Science 302:841

    Article  PubMed  CAS  Google Scholar 

  6. Spillantini MG, Schmidt ML, Lee VM-Y, Trojanowski JQ, Jakes R, Goedert M (1997) α-Synuclein in Lewy bodies. Nature 388:839–840

    Article  PubMed  CAS  Google Scholar 

  7. Baba M, Nakajo S, Tu PH et al (1998) Aggregation of α-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 152:879–884

    PubMed  CAS  Google Scholar 

  8. Seidel K, Schols L, Nuber S et al (2010) First appraisal of brain pathology owing to A30P mutant alpha-synuclein. Ann Neurol 67:684–689

    Article  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 α-synuclein. Neurology 51:887–889

    Article  PubMed  CAS  Google Scholar 

  10. Wakabayashi K, Yoshimot M, Fukushima T et al (1999) Widespread occurrence of α-synuclein/NACP-immunoreactive neuronal inclusions in juvenile- and adult-onset Hallervorden–Spatz disease with Lewy bodies. Neuropathol Appl Neurobiol 125:363–368

    Article  Google Scholar 

  11. Paisan-Ruiz C, Li A, Schneider SA et al (2012) Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiol Aging 33:814–823

    Article  PubMed  CAS  Google Scholar 

  12. Wong K, Sidransky E, Verma A et al (2004) Neuropathology provides clue to the pathophysiology of Gaucher disease. Mol Genet Metab 82:192–207

    Article  PubMed  CAS  Google Scholar 

  13. Hamilton R (2000) Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using α-synuclein immunohistochemistry. Brain Pathol 10:378–384

    Article  PubMed  CAS  Google Scholar 

  14. Saito Y, Suzuki K, Hulette CM, Murayama S (2004) Aberrant phosphorylation of alpha-synuclein in human Niemann–Pick type C1 disease. J Neuroapthol Exp Neurol 63:323–328

    CAS  Google Scholar 

  15. Suzuki K, Iseki E, Togo T et al (2007) Neuronal and glial accumulation of α- and β-synucleins in human lipidoses. Acta Neuropathol 114:481–489

    Article  PubMed  CAS  Google Scholar 

  16. Winder-Rhodes SE, Garcia-Reitbock P, Ban M et al (2012) Genetic and pathological links between Parkinson’s disease and the lysosomal disorder Sanfilippo syndrome. Mov Disord 27:312–315

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  18. Tu P-H, Galvin JE, Baba M et al (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α-synuclein. Ann Neurol 44:415–422

    Article  PubMed  CAS  Google Scholar 

  19. Arima K, Uéda K, Sunohara N et al (1998) NACP/α-synuclein immunoreactivity in fibrillary components of neuronal and oligodendroglial cytoplasmic inclusions in the pontine nuclei in multiple system atrophy. Acta Neuropathol 96:439–444

    Article  PubMed  CAS  Google Scholar 

  20. Lewy FH (1912) Paralysis agitans. I. Pathologische Anatomie. In: Lewandowsky M (ed) Hundbuch der Neurologie III. Springer, Berlin, pp 920–933

    Google Scholar 

  21. Tretiakoff MC (1919) Contribution a l’étude de l’anatomie pathologique de Locus Niger de Soemmerling. Université de Paris.

  22. Wakabayashi K, Takahashi H, Obata K, Ikuta F (1992) Immunocytochemical localization of synaptic vesicle-specific protein in Lewy body-containing neurons in Parkinson’s disease. Neurosci Lett 138:237–240

    Article  PubMed  CAS  Google Scholar 

  23. Duffy PE, Tennyson VM (1965) Phase and electron microscopic observations of Lewy bodies and melanin granules in the substantia nigra and locus caeruleus in Parkinson’s disease. J Neuropathol Exp Neurol 24:398–414

    Article  Google Scholar 

  24. Kosaka K (1978) Lewy bodies in cerebral cortex. Report of three cases. Acta Neuropathol 42:127–134

    Article  PubMed  CAS  Google Scholar 

  25. Lowe J, Blanchard A, Morrell K et al (1988) Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson’s disease, Pick’s disease, and Alzheimer’s disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and Mallory bodies in alcoholic liver disease. J Pathol 155:9–15

    Article  PubMed  CAS  Google Scholar 

  26. Kuzuhara S, Mori H, Izumiyama N, Yoshimura M, Ihara Y (1988) Lewy bodies are ubiquitinated. A light and electron microscopic immunocytochemical study. Acta Neuropathol 75:345–353

    Article  PubMed  CAS  Google Scholar 

  27. Fujiwara H, Hasegawa M, Dohmae N et al (2002) α-Synuclein is phosphorylated in synucleinopathy lesions. Nature Cell Biol 4:160–164

    Article  PubMed  CAS  Google Scholar 

  28. Saito Y, Kawashima A, Ruberu NN et al (2003) Accumulation of phosphorylated α-synuclein in aging human brain. J Neuropathol Exp Neurol 62:644–654

    PubMed  CAS  Google Scholar 

  29. Dickson DW, Ruan D, Crystal H et al (1991) Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD) from Alzheimer’s disease: light and electron microscopic immunocytochemistry of CA2–3 neurites specific to DLBD. Neurology 41:1402–1409

    Article  PubMed  CAS  Google Scholar 

  30. Wakabayashi K, Takahashi H (1996) Gallyas-positive, tau-negative glial inclusions in Parkinson’s disease midbrain. Neurosci Lett 217:133–136

    Article  PubMed  CAS  Google Scholar 

  31. Arai T, Uéda K, Ikeda K et al (1999) Argyrophilic glial inclusions in the midbrain of patients with Parkinson’s disease and diffuse Lewy body disease are immunopositive for NACP/α-synuclein. Neurosci Lett 259:83–86

    Article  PubMed  CAS  Google Scholar 

  32. Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H (2000) NACP/α-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson’s disease brains. Acta Neuropathol 99:14–20

    Article  PubMed  CAS  Google Scholar 

  33. Piao Y-S, Wakabayashi K, Hayashi S, Yoshimoto M, Takahashi H (2000) Aggregation of α-synuclein/NACP in the neuronal and glial cells in diffuse Lewy body disease: a survey of six patients. Clin Neuropathol 19:163–169

    PubMed  CAS  Google Scholar 

  34. Hishikawa N, Hashizume Y, Yoshida M, Sobue G (2001) Widespread occurrence of argyrophilic glial inclusions in Parkinson’s disease. Neuropathol Appl Neurobiol 27:362–372

    Article  PubMed  CAS  Google Scholar 

  35. Piao Y-S, Mori F, Hayashi S et al (2003) α-Synuclein pathology affecting Bergmann glia of the cerebellum in patients with α-synucleinopathies. Acta Neuropathol 105:403–409

    PubMed  Google Scholar 

  36. Sengoku R, Saito Y, Ikemura M et al (2008) Incidence and extent of Lewy body-related α-synucleinopathy in aging human olfactory bulb. J Neuropathol Exp Neurol 67:1072–1083

    Article  PubMed  Google Scholar 

  37. Langston JW, Forno LS (1978) The hypothalamus in Parkinson disease. Ann Neurol 3:129–133

    Article  PubMed  CAS  Google Scholar 

  38. Homma T, Mochizuki Y, Mizutani T (2012) Phosphorylated α-synuclein immunoreactivity in the posterior pituitary lobe. Neuropathology. doi:10.1111/j.1440-1789.2011.01273.x

  39. den Hartog Jager WA, Bethlem J (1960) The distribution of Lewy bodies in the central and autonomic nervous systems in idiopathic paralysis agitans. J Neurol Neurosurg Psychiatry 23:283–290

    Article  Google Scholar 

  40. Ohama E, Ikuta F (1976) Parkinson’s disease. Distribution of Lewy bodies and monoamine neurons system. Acta Neuropathol 34:311–319

    Article  PubMed  CAS  Google Scholar 

  41. Braak H, Rüb U, Sandmann-Keil D et al (2000) Parkinson’s disease: affection of brain stem nuclei controlling premotor and motor neurons of the somatomotor system. Acta Neuropathol 99:489–495

    Article  PubMed  CAS  Google Scholar 

  42. Kakita A, Takahashi H, Homma Y, Ikuta F (1994) Lewy bodies in the cerebellar dentate nucleus of a patient with Parkinson’s disease. Pathol Int 44:878–880

    Article  PubMed  CAS  Google Scholar 

  43. Mori F, Piao Y-S, Hayashi S et al (2003) α-Synuclein accumulates in Purkinje cells in Lewy body disease but not in multiple system atrophy. J Neuropathol Exp Neurol 62:812–819

    PubMed  CAS  Google Scholar 

  44. Oyanagi K, Wakabayashi K, Ohama E et al (1990) Lewy bodies in the lower sacral parasympathetic neurons of a patient with Parkinson’s disease. Acta Neuropathol 80:558–559

    Article  PubMed  CAS  Google Scholar 

  45. Wakabayashi K, Takahashi H (1997) The intermediolateral nucleus and Clarke’s column in Parkinson’s disease. Acta Neuropathol 94:287–289

    Article  PubMed  CAS  Google Scholar 

  46. Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K (2007) Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 113:421–429

    Article  PubMed  Google Scholar 

  47. Tamura T, Yoshida M, Hashizume Y, Sobue G (2012) Lewy body-related α-synucleinopathy in the spinal cord of cases with incidental Lewy body disease. Neuropathology 32:13–22

    Article  PubMed  Google Scholar 

  48. Braak H, Braak E, Yilmazer D et al (1994) Amygdala pathology in Parkinson’s disease. Acta Neuropathol 88:493–500

    Article  PubMed  CAS  Google Scholar 

  49. Wakabayashi K, Hansen LA, Masliah E (1995) Cortical Lewy body-containing neurons are pyramidal cells: laser confocal imaging of double-immunolabeled sections with anti-ubiquitin and SMI32. Acta Neuropathol 89:404–408

    Article  PubMed  CAS  Google Scholar 

  50. Forno LS, Norville RL (1976) Ultrastructure of Lewy bodies in the stellate ganglion. Acta Neuropathol 34:183–197

    Article  PubMed  CAS  Google Scholar 

  51. Wakabayashi K, Takahashi H, Takeda S, Ohama E, Ikuta F (1988) Parkinson’s disease: the presence of Lewy bodies in Auerbach’s and Meissner’s plexuses. Acta Neuropathol 76:217–221

    Article  PubMed  CAS  Google Scholar 

  52. Braak H, de Vos RAI, Bohl J, Del Tredici K (2006) Gastric α-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 396:67–72

    Article  PubMed  CAS  Google Scholar 

  53. Lebouvier T, Neunlist M, des Varannes SB et al (2010) Colonic biopsies to assess the neuropathology of Parkinson’s disease and its relationship with symptoms. PLoS ONE 5:e12728

    Article  PubMed  CAS  Google Scholar 

  54. Beach TG, Adler CH, Sue LI et al (2010) Multi-organ distribution of phosphorylated α-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119:689–702

    Article  PubMed  CAS  Google Scholar 

  55. Iwanaga K, Wakabayashi K, Yoshimoto M et al (1999) Lewy body-type degeneration in cardiac plexus in Parkinson’s and incidental Lewy body diseases. Neurology 52:1269–1271

    Article  PubMed  CAS  Google Scholar 

  56. Orimo S, Uchihara T, Nakamura A et al (2008) Axonal α-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson’s disease. Brain 131:642–650

    Article  PubMed  Google Scholar 

  57. Wakabayashi K, Takahashi H (1997) Neuropathology of autonomic nervous system in Parkinson’s disease. Eur Neurol 38(Suppl 2):2–7

    Article  PubMed  Google Scholar 

  58. Minguez-Castellanos A, Chamorro CE, Escamilla-Sevilla F et al (2007) Do α-synuclein aggregates in autonomic plexuses predate Lewy body disorders? Neurology 68:2012–2018

    Article  PubMed  CAS  Google Scholar 

  59. Fumimura Y, Ikemura M, Saito Y et al (2007) Analysis of the adrenal gland is useful for evaluating pathology of the peripheral autonomic nervous system in Lewy body disease. J Neuropathol Exp Neurol 66:354–362

    Article  PubMed  Google Scholar 

  60. Del Tredici K, Hawkes CH, Ghebremedhin E, Braak H (2010) Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson’s disease. Acta Neuropathol 119:703–707

    Article  PubMed  Google Scholar 

  61. Ikemura M, Saito Y, Sengoku R et al (2008) Lewy body pathology involves cutaneous nerves. J Neuropathol Exp Neurol 67:945–953

    Article  PubMed  Google Scholar 

  62. Miki Y, Tomiyama M, Ueno T et al (2010) Clinical availability of skin biopsy in the diagnosis of Parkinson’s disease. Neurosci Lett 469:357–359

    Article  PubMed  CAS  Google Scholar 

  63. Wakabayashi K, Mori F, Tanji K, Orimo S, Takahashi H (2010) Involvement of the peripheral nervous system in synucleinopathies, tauopathies and other neurodegenerative proteinopathies of the brain. Acta Neuropathol 120:1–12

    Article  PubMed  Google Scholar 

  64. Langston JW (2006) The Parkinson’s complex: Parkinsonism is just the tip of the iceberg. Ann Neurol 59:591–596

    Article  PubMed  Google Scholar 

  65. Lim SY, Fox SH, Lang AE (2009) Overview of the extranigral aspects of Parkinson disease. Arch Neurol 66:167–172

    Article  PubMed  Google Scholar 

  66. Ross GW, Abbott RD, Petrovitch H et al (2006) Association of olfactory dysfunction with incidental Lewy bodies. Mov Disord 21:2062–2067

    Article  PubMed  Google Scholar 

  67. Abbott RD, Ross GW, Petrovitch H et al (2007) Bowel movement frequency in late-life and incidental Lewy bodies. Mov Disord 22:1581–1586

    Article  PubMed  Google Scholar 

  68. Beach TG, Adler CH, Sue LI et al (2008) Reduced striatal tyrosine hydroxylase in incidental Lewy body disease. Acta Neuropathol 115:445–451

    Article  PubMed  CAS  Google Scholar 

  69. DelleDonne A, Klos J, Fujishiro H et al (2008) Incidental Lewy body disease and preclinical Parkinson’s disease. Arch Neurol 65:1074–1080

    Article  PubMed  Google Scholar 

  70. Dickson DW, Fujishiro H, DelleDonne A et al (2008) Evidence that incidental Lewy body disease is pre-symptomatic Parkinson’s disease. Acta Neuropathol 115:437–444

    Article  PubMed  Google Scholar 

  71. Caviness JN, Adler CH, Hentz JG et al (2011) Incidental Lewy body disease: electrophysiological findings suggesting pre-clinical Lewy body disorders. Clin Neurophysiol 122:2426–2432

    Article  PubMed  Google Scholar 

  72. Braak H, Del Tredici K, Rüb U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211

    Article  PubMed  Google Scholar 

  73. Braak H, Bohl JR, Müller CM et al (2006) The staging procedure for the inclusion body pathology associated with sporadic Parkinson’s disease reconsidered. Mov Disord 21:2042–2051

    Article  PubMed  Google Scholar 

  74. McKeith IG, Dickson DW, Lowe J et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872

    Article  PubMed  CAS  Google Scholar 

  75. Mori F, Tanji K, Zhang H, Kakita A, Takahashi H, Wakabayashi K (2008) α-Synuclein pathology in the neostriatum in Parkinson’s disease. Acta Neuropathol 115:453–459

    Article  PubMed  CAS  Google Scholar 

  76. Braak H, Müller CM, Rüb U et al (2006) Pathology associated with sporadic Parkinson’s disease-where does it end? J Neural Transm Suppl 70:89–97

    Article  PubMed  Google Scholar 

  77. Attems J, Jellinger KA (2008) The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson’s disease. Neuropathol Appl Neurobiol 34:466–467

    Article  PubMed  CAS  Google Scholar 

  78. Parkkinen L, Pirttila T, Alafuzoff I (2008) Applicability of current staging/categorization of α-synuclein pathology and their clinical relevance. Acta Neuropathol 115:399–407

    Article  PubMed  Google Scholar 

  79. Dickson DW, Uchikado H, Fujishiro H et al (2010) Evidence in favor of Braak staging of Parkinson’s disease. Mov Disord 25(suppl 1):S78–S82

    Article  PubMed  Google Scholar 

  80. Fujimi K, Sasaki K, Noda K et al (2008) Clinicopathological outline of dementia with Lewy bodies applying the revised criteria: the Hisayama study. Brain Pathol 18:317–325

    Article  PubMed  Google Scholar 

  81. Jellinger KA (2008) A critical reappraisal of current staging of Lewy-related pathology in human brain. Acta Neuropathol 116:1–16

    Article  PubMed  CAS  Google Scholar 

  82. Kalaitzakis ME, Graeber MB, Gentleman SM et al (2008) The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson’s disease: a critical analysis of α-synuclein staging. Neuropathol Appl Neurobiol 34:284–295

    Article  PubMed  CAS  Google Scholar 

  83. Leverenz JB, Hamilton R, Tsuang DW et al (2008) Empiric refinement of the pathologic assessment of Lewy-related pathology in the dementia patient. Brain Pathol 18:220–224

    Article  PubMed  Google Scholar 

  84. Zaccai J, Brayne C, McKeith I et al (2008) Patterns and stages of α-synucleinopathy. Relevance in a population-based cohort. Neurology 70:1042–1048

    Article  PubMed  CAS  Google Scholar 

  85. Beach TG, Adler CH, Lue L et al (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117:613–634

    Article  PubMed  Google Scholar 

  86. Beach TG, White CL 3rd, Hladik CL et al (2009) Olfactory bulb α-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol 117:169–174

    Article  PubMed  CAS  Google Scholar 

  87. Pappolla MA, Shank DL, Alzofon J, Dudley AW (1988) Colloid (hyaline) inclusion bodies in the central nervous system: their presence in the substantia nigra is diagnostic of Parkinson’s disease. Hum Pathol 19:27–31

    Article  PubMed  CAS  Google Scholar 

  88. Gibb WR, Scott T, Lees AJ (1991) Neuronal inclusions of Parkinson’s disease. Mov Disord 6:2–11

    Article  PubMed  CAS  Google Scholar 

  89. Dale GE, Probst A, Luthert P, Martin J, Anderton BH, Leigh PN (1992) Relationships between Lewy bodies and pale bodies in Parkinson’s disease. Acta Neuropathol 83:525–529

    Article  PubMed  CAS  Google Scholar 

  90. Takahashi H, Iwanaga K, Egawa S, Ikuta F (1994) Ultrastructural relationship between Lewy bodies and pale bodies studied in locus ceruleus neurons of a non-parkinsonian patient. Neuropathology 14:73–80

    Article  Google Scholar 

  91. Wakabayashi K, Hayashi S, Kakita A et al (1998) Accumulation of α-synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy. Acta Neuropathol 96:445–452

    Article  PubMed  CAS  Google Scholar 

  92. Wakabayashi K, Mori F, Takahashi H (2006) Progression patterns of neuronal loss and Lewy body pathology in the substantia nigra in Parkinson’s disease. Parkinsonism Relat Disord 12(suppl 2):S92–98

    Article  Google Scholar 

  93. Kuusisto E, Parkkinen L, Alafuzoff I (2003) Morphogenesis of Lewy bodies: dissimilar incorporation of α-synuclein, ubiquitin, and p62. J Neuropathol Exp Neurol 62:1241–1253

    PubMed  CAS  Google Scholar 

  94. Kovacs GG, Wagner U, Dumont B et al (2012) An antibody with high reactivity for disease-associated α-synuclein reveals extensive brain pathology. Acta Neuropathol

  95. Katsuse O, Iseki E, Marui W, Kosaka K (2003) Developmental stages of cortical Lewy bodies and their relation to axonal transport blockage in brains of patients with dementia with Lewy bodies. J Neurol Sci 211:29–35

    Article  PubMed  CAS  Google Scholar 

  96. Kanazawa T, Adachi E, Orimo S, Nakamura A, Mizusawa H, Uchihara T (2012) Pale neurites, premature α-synuclein aggregates with centripetal extension from axonal collaterals. Brain Pathol 22:67–78

    Article  PubMed  Google Scholar 

  97. Mori F, Nishie M, Kakita A, Yoshimoto M, Takahashi H, Wakabayashi K (2006) Relationship among α-synuclein accumulation, dopamine synthesis, and neurodegeneration in Parkinson disease substantia nigra. J Neuropathol Exp Neurol 65:808–815

    Article  PubMed  CAS  Google Scholar 

  98. Wakabayashi K, Tanji K, Mori F, Takahashi H (2007) The Lewy body in Parkinson’s disease: molecules implicated in the formation and degradation of α-synuclein aggregates. Neuropathology 27:494–506

    Article  PubMed  Google Scholar 

  99. Goldman JE, Yen SH, Chiu FC, Peress NS (1983) Lewy bodies of Parkinson’s disease contain neurofilament antigens. Science 221:1082–1084

    Article  PubMed  CAS  Google Scholar 

  100. Schmidt ML, Murray J, Lee VM, Hill WD, Wertkin A, Trojanowski JQ (1991) Epitope map of neurofilament protein domains in cortical and peripheral nervous system Lewy bodies. Am J Pathol 139:53–65

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  102. Kawamoto Y, Akiguchi I, Nakamura S, Honjyo Y, Shibasaki H, Budka H (2002) 14-3-3 proteins in Lewy bodies in Parkinson disease and diffuse Lewy body disease brains. J Neuropathol Exp Neurol 61:245–253

    PubMed  CAS  Google Scholar 

  103. Ubl A, Berg D, Holzmann C et al (2002) 14-3-3 protein is a component of Lewy bodies in Parkinson’s disease—mutation analysis and association studies of 14-3-3 eta. Brain Res Mol Brain Res 108:33–39

    Article  PubMed  CAS  Google Scholar 

  104. Gai WP, Blumbergs PC, Blessing WW (1996) Microtubule-associated protein 5 is a component of Lewy bodies and Lewy neurites in the brainstem and forebrain regions affected in Parkinson’s disease. Acta Neuropathol 91:78–81

    Article  PubMed  CAS  Google Scholar 

  105. 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 α-synuclein filaments. J Biol Chem 275:21500–21507

    Article  PubMed  CAS  Google Scholar 

  106. 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

    Article  PubMed  CAS  Google Scholar 

  107. Wakabayashi K, Engelender S, Tanaka Y et al (2002) Immunocytochemical localization of synphilin-1, an α-synuclein-associated protein, in neurodegenerative disorders. Acta Neuropathol 103:209–214

    Article  PubMed  CAS  Google Scholar 

  108. Bandopadhyay R, Kingsbury AE, Muqit MM et al (2005) Synphilin-1 and parkin show overlapping expression patterns in human brain and form aggresomes in response to proteasomal inhibition. Neurobiol Dis 20:401–411

    Article  PubMed  CAS  Google Scholar 

  109. Galloway PG, Bergeron C, Perry G (1989) The presence of tau distinguishes Lewy bodies of diffuse Lewy body disease from those of idiopathic Parkinson disease. Neurosci Lett 100:6–10

    Article  PubMed  CAS  Google Scholar 

  110. Ishizawa T, Mattila P, Davies P, Wang D, Dickson DW (2003) Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J Neuropathol Exp Neurol 62:389–397

    PubMed  CAS  Google Scholar 

  111. Hishikawa N, Niwa J, Doyu M et al (2003) Dorfin localizes to the ubiquitylated inclusions in Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, and amyotrophic lateral sclerosis. Am J Pathol 163:609–619

    Article  PubMed  CAS  Google Scholar 

  112. 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

    Article  PubMed  CAS  Google Scholar 

  113. Nagao M, Hayashi H (2009) Glycogen synthase kinase-3beta is associated with Parkinson’s disease. Neurosci Lett 449:103–107

    Article  PubMed  CAS  Google Scholar 

  114. Tanji K, Tanaka T, Mori F et al (2006) NUB1 suppresses the formation of Lewy body-like inclusions by proteasomal degradation of synphilin-1. Am J Pathol 169:553–565

    Article  PubMed  CAS  Google Scholar 

  115. Tanji K, Mori F, Kakita A et al (2007) Immunohistochemical localization of NUB1, a synphilin-1-binding protein, in neurodegenerative disorders. Acta Neuropathol 114:365–371

    Article  PubMed  CAS  Google Scholar 

  116. Schlossmacher MG, Frosch MP, Gai WP et al (2002) Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies. Am J Pathol 160:1655–1667

    Article  PubMed  CAS  Google Scholar 

  117. Murakami T, Shoji M, Imai Y et al (2004) Pael-R is accumulated in Lewy bodies of Parkinson’s disease. Ann Neurol 55:439–442

    Article  PubMed  CAS  Google Scholar 

  118. Ryo A, Togo T, Nakai T et al (2006) Prolyl-isomerase Pin1 accumulates in Lewy bodies of Parkinson disease and facilitates formation of α-synuclein inclusions. J Biol Chem 281:4117–4125

    Article  PubMed  CAS  Google Scholar 

  119. Liani E, Eyal A, Avraham E et al (2004) Ubiquitylation of synphilin-1 and α-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson’s disease. Proc Natl Acad Sci U S A 101:5500–5505

    Article  PubMed  CAS  Google Scholar 

  120. McNaught KS, Shashidharan P, Perl DP, Jenner P, Olanow CW (2002) Aggresome-related biogenesis of Lewy bodies. Eur J Neurosci 16:2136–2148

    Article  PubMed  Google Scholar 

  121. Zucchelli S, Codrich M, Marcuzzi F et al (2010) TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson’s disease brains. Hum Mol Genet 19:3759–3770

    Article  PubMed  CAS  Google Scholar 

  122. Tanji K, Kamitani T, Mori F, Kakita A, Takahashi H, Wakabayashi K (2010) TRIM9, a novel brain-specific E3 ubiquitin ligase, is repressed in the brain of Parkinson’s disease and dementia with Lewy bodies. Neurobiol Dis 38:210–218

    Article  PubMed  CAS  Google Scholar 

  123. Fergusson J, Landon M, Lowe J et al (1996) Pathological lesions of Alzheimer’s disease and dementia with Lewy bodies brains exhibit immunoreactivity to an ATPase that is a regulatory subunit of the 26 S proteasome. Neurosci Lett 219:167–170

    Article  PubMed  CAS  Google Scholar 

  124. Ii K, Ito H, Tanaka K, Hirano A (1997) Immunocytochemical co-localization of the proteasome in ubiquitinated structures in neurodegenerative diseases and the elderly. J Neuropathol Exp Neurol 56:125–131

    Article  PubMed  CAS  Google Scholar 

  125. Lindersson E, Beedholm R, Hojrup P et al (2004) Proteasomal inhibition by α-synuclein filaments and oligomers. J Biol Chem 279:12924–12934

    Article  PubMed  CAS  Google Scholar 

  126. Noda K, Kitami T, Gai WP et al (2005) Phosphorylated IκBα is a component of Lewy body of Parkinson’s disease. Biochem Biophys Res Commun 331:309–317

    Article  PubMed  CAS  Google Scholar 

  127. Takahashi-Fujigasaki J, Fujigasaki H (2006) Histone deacetylase (HDAC) 4 involvement in both Lewy and Marinesco bodies. J Neuropathol Appl Neurobiol 32:562–566

    Article  CAS  Google Scholar 

  128. Kwak S, Masaki T, Ishiura S, Sugita H (1991) Multicatalytic proteinase is present in Lewy bodies and neurofibrillary tangles in diffuse Lewy body disease brains. Neurosci Lett 128:21–24

    Article  PubMed  CAS  Google Scholar 

  129. Masaki T, Ishiura S, Sugita H, Kwak S (1994) Multicatalytic proteinase is associated with characteristic oval structures in cortical Lewy bodies: an immunocytochemical study with light and electron microscopy. J Neurol Sci 122:127–134

    Article  PubMed  CAS  Google Scholar 

  130. Dil Kuazi A, Kito K, Abe Y, Shin RW, Kamitani T, Ueda N (2003) NEDD8 protein is involved in ubiquitinated inclusion bodies. J Pathol 199:259–266

    Article  PubMed  CAS  Google Scholar 

  131. Mori F, Nishie M, Piao YS et al (2005) Accumulation of NEDD8 in neuronal and glial inclusions of neurodegenerative disorders. Neuropathol Appl Neurobiol 31:53–61

    Article  PubMed  CAS  Google Scholar 

  132. Corti O, Hampe C, Koutnikova H et al (2003) The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration. Hum Mol Genet 12:1427–1437

    Article  PubMed  CAS  Google Scholar 

  133. Lowe J, McDermott H, Landon M, Mayer RJ, Wilkinson KD (1990) Ubiquitin carboxyl-terminal hydrolase (PGP 9.5) is selectively present in ubiquitinated inclusion bodies characteristic of human neurodegenerative diseases. J Pathol 161:153–160

    Article  PubMed  CAS  Google Scholar 

  134. Crews L, Spencer B, Desplats P et al (2010) Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS One 5:e9313

    Article  PubMed  CAS  Google Scholar 

  135. Higashi S, Moore DJ, Minegishi M et al (2011) Localization of MAP1-LC3 in vulnerable neurons and Lewy bodies in brains of patients with dementia with Lewy bodies. J Neuropathol Exp Neurol 70:264–280

    Article  PubMed  CAS  Google Scholar 

  136. Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K (2011) Alteration of autophagosomal protein (LC3, GABARAP and GATE-16) in Lewy body disease. Neurobiol Dis 43:690–697

    Article  PubMed  CAS  Google Scholar 

  137. Goker-Alpan O, Stubblefield BK, Giasson BI, Sidransky E (2010) Glucocerebrosidase is present in α-synuclein inclusions in Lewy body disorders. Acta Neuropathol 120:641–649

    Article  PubMed  CAS  Google Scholar 

  138. Odagiri S, Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K (2012) Autophagic adapter protein NBR1 is localized in Lewy bodies and glial cytoplasmic inclusions and is involved in aggregate formation in α-synucleinopathy. Acta Neuropathol (in press)

  139. Kawaguchi Y, Kovacs JJ, McLaurin A et al (2003) The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115:727–738

    Article  PubMed  CAS  Google Scholar 

  140. Miki Y, Mori F, Tanji K, Kakita A, Takahashi H, Wakabayashi K (2011) Accumulation of histone deacetylase 6, an aggresome-related protein, is specific to Lewy bodies and glial cytoplasmic inclusions. Neuropathology 31:561–568

    Article  PubMed  Google Scholar 

  141. Shin Y, Klucken J, Patterson C, Hyman BT, McLean PJ (2005) The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates α-synuclein degradation decisions between proteasomal and lysosomal pathways. J Biol Chem 280:23727–23734

    Article  PubMed  CAS  Google Scholar 

  142. Sasaki K, Doh-ura K, Wakisaka Y, Iwaki T (2002) Clusterin/apolipoprotein J is associated with cortical Lewy bodies: immunohistochemical study in cases with α-synucleinopathies. Acta Neuropathol 104:225–230

    Article  PubMed  CAS  Google Scholar 

  143. Durrenberger PF, Filiou MD, Moran LB et al (2009) DnaJB6 is present in the core of Lewy bodies and is highly up-regulated in parkinsonian astrocytes. J Neurosci Res 87:238–245

    Article  PubMed  CAS  Google Scholar 

  144. Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM (2002) Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295:865–868

    Article  PubMed  CAS  Google Scholar 

  145. McLean PJ, Kawamata H, Shariff S et al (2002) TorsinA and heat shock proteins act as molecular chaperones: suppression of α-synuclein aggregation. J Neurochem 83:846–854

    Article  PubMed  CAS  Google Scholar 

  146. Shashidharan P, Good PF, Hsu A, Perl DP, Brin MF, Olanow CW (2000) TorsinA accumulation in Lewy bodies in sporadic Parkinson’s disease. Brain Res 877:379–381

    Article  PubMed  CAS  Google Scholar 

  147. Sharma N, Hewett J, Ozelius LJ et al (2001) A close association of torsinA and α-synuclein in Lewy bodies. A fluorescence resonance energy transfer study. Am J Pathol 159:339–344

    Article  PubMed  CAS  Google Scholar 

  148. Yamada T, Horisberger MA, Kawaguchi N, Moroo I, Toyoda T (1994) Immunohistochemistry using antibodies to α-interferon and its induced protein, MxA, in Alzheimer’s and Parkinson’s disease brain tissues. Neurosci Lett 181:61–64

    Article  PubMed  CAS  Google Scholar 

  149. Castellani R, Smith MA, Richey PL, Perry G (1996) Glycoxidation and oxidative stress in Parkinson disease and diffuse Lewy body disease. Brain Res 737:195–200

    Article  PubMed  CAS  Google Scholar 

  150. Münch G, Lüth HJ, Wong A et al (2000) Crosslinking of α-synuclein by advanced glycation endproducts—an early pathophysiological step in Lewy body formation? J Chem Neuroanat 20:253–257

    Article  PubMed  Google Scholar 

  151. Kokoulina P, Rohn TT (2010) Caspase-cleaved transactivation response DNA-binding protein 43 in Parkinson’s disease and dementia with Lewy bodies. Neurodegenerative Dis 7:243–250

    CAS  Google Scholar 

  152. Bandopadhyay R, Kingsbury AE, Cookson MR et al (2004) The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson’s disease. Brain 127:420–430

    Article  PubMed  Google Scholar 

  153. Jin J, Meredith GE, Chen L et al (2005) Quantitative proteomic analysis of mitochondrial proteins: relevance to Lewy body formation and Parkinson’s disease. Brain Res Mol Brain Res 134:119–138

    Article  PubMed  CAS  Google Scholar 

  154. Su B, Liu H, Wang X et al (2009) Ectopic localization of FOXO3a protein in Lewy bodies in Lewy body dementia and Parkinson’s disease. Mol Neurodegeneration 4:32

    Article  CAS  Google Scholar 

  155. Power JHT, Blumbergs PC (2009) Cellular glutathione peroxidase in human brain: cellular distribution, and its potential role in the degradation of Lewy bodies in Parkinson’s disease and dementia with Lewy bodies. Acta Neuropathol 117:63–73

    Article  PubMed  CAS  Google Scholar 

  156. Schipper HM, Liberman A, Stopa EG (1998) Neural heme oxygenase-1 expression in idiopathic Parkinson’s disease. Exp Neurol 150:60–68

    Article  PubMed  CAS  Google Scholar 

  157. Lowe J, Landon M, Pike I, Spendlove I, McDermott H, Mayer RJ (1990) Dementia with β-amyloid deposition: involvement of αB-crystallin supports two main diseases. Lancet 336:515–516

    Article  PubMed  CAS  Google Scholar 

  158. Lowe J, McDermott H, Pike I, Spendlove I, Landon M, Mayer RJ (1992) αB crystallin expression in non-lenticular tissues and selective presence in ubiquitinated inclusion bodies in human disease. J Pathol 166:61–68

    Article  PubMed  CAS  Google Scholar 

  159. Nishiyama K, Murayama S, Shimizu J et al (1995) Cu/Zn superoxide dismutase-like immunoreactivity is present in Lewy bodies from Parkinson disease: a light and electron microscopic immunocytochemical study. Acta Neuropathol 89:471–474

    Article  PubMed  CAS  Google Scholar 

  160. Iwatsubo T, Nakano I, Fukunaga K, Miyamoto E (1991) Ca2+/calmodulin-dependent protein kinase II immunoreactivity in Lewy bodies. Acta Neuropathol 82:159–163

    Article  PubMed  CAS  Google Scholar 

  161. Ryu MY, Kim DW, Arima K, Mouradian MM, Kim SU, Lee G (2008) Localization of CKII β subunits in Lewy bodies of Parkinson’s disease. J Neurol Sci 266:9–12

    Article  PubMed  CAS  Google Scholar 

  162. Brion JP, Couck AM (1995) Cortical and brainstem-type Lewy bodies are immunoreactive for the cyclin-dependent kinase 5. Am J Pathol 147:1465–1476

    PubMed  CAS  Google Scholar 

  163. Takahashi M, Iseki E, Kosaka K (2000) Cyclin-dependent kinase 5 (Cdk5) associated with Lewy bodies in diffuse Lewy body disease. Brain Res 862:253–256

    Article  PubMed  CAS  Google Scholar 

  164. Ferrer I, Blanco R, Carmona M et al (2001) Active, phosphorylation-dependent mitogen-activated protein kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson’s disease and Dementia with Lewy bodies. J Neural Transm 108:1383–1396

    Article  PubMed  CAS  Google Scholar 

  165. Arawaka S, Wada M, Goto S et al (2006) The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson’s disease. J Neurosci 26:9227–9238

    Article  PubMed  CAS  Google Scholar 

  166. Greggio E, Jain S, Kingsbury A et al (2006) Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis 23:329–341

    Article  PubMed  CAS  Google Scholar 

  167. Miklossy J, Arai T, Guo JP et al (2006) LRRK2 expression in normal and pathologic human brain and in human cell lines. J Neuropathol Exp Neurol 65:953–963

    Article  PubMed  CAS  Google Scholar 

  168. Zhu X, Siedlak SL, Smith MA, Perry G, Chen SG (2006) LRRK2 protein is a component of Lewy bodies. Ann Neurol 60:617–618

    Article  PubMed  Google Scholar 

  169. Zhu X, Babar A, Siedlak SL et al (2006) LRRK2 in Parkinson’s disease and dementia with Lewy bodies. Mol Neurodegener 1:17–25

    Article  PubMed  CAS  Google Scholar 

  170. Gandhi S, Muqit MM, Stanyer L et al (2006) PINK1 protein in normal human brain and Parkinson’s disease. Brain 129:1720–1731

    Article  PubMed  CAS  Google Scholar 

  171. Togo T, Iseki E, Marui W, Akiyama H, Uéda K, Kosaka K (2001) Glial involvement in the degeneration process of Lewy body-bearing neurons and the degradation process of Lewy bodies in brains of dementia with Lewy bodies. J Neurol Sci 184:71–75

    Article  PubMed  CAS  Google Scholar 

  172. Nakamura S, Kawamoto Y, Nakano S, Akiguchi I, Kimura J (1997) p35nck5a and cyclin-dependent kinase 5 colocalize in Lewy bodies of brains with Parkinson’s disease. Acta Neuropathol 94:153–157

    Article  PubMed  CAS  Google Scholar 

  173. Shimohama S, Perry G, Richey P et al (1993) Abnormal accumulation of phospholipase C-δ in filamentous inclusions of human neurodegenerative diseases. Neurosci Lett 162:183–186

    Article  PubMed  CAS  Google Scholar 

  174. Junn E, Ronchetti RD, Quezado MM, Kim SY, Mouradian MM (2003) Tissue transglutaminase-induced aggregation of α-synuclein: implications for Lewy body formation in Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci U S A 100:2047–2052

    Article  PubMed  CAS  Google Scholar 

  175. 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 47:654–663

    Article  PubMed  CAS  Google Scholar 

  176. Fukuda T, Tanaka J, Watabe K, Numoto RT, Minamitani M (1993) Immunohistochemistry of neuronal inclusions in the cerebral cortex and brain-stem in Lewy body disease. Acta Pathol Jpn 43:545–551

    PubMed  CAS  Google Scholar 

  177. 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

    Article  PubMed  Google Scholar 

  178. Ihara M, Tomimoto H, Kitayama H et al (2003) Association of the cytoskeletal GTP-binding protein Sept4/H5 with cytoplasmic inclusions found in Parkinson’s disease and other synucleinopathies. J Biol Chem 278:24095–24102

    Article  PubMed  CAS  Google Scholar 

  179. Kovács GG, László L, Kovács J et al (2004) Natively unfolded tubulin polymerization promoting protein TPPP/p25 is a common marker of alpha-synucleinopathies. Neurobiol Dis 17:155–162

    Article  PubMed  CAS  Google Scholar 

  180. Lindersson E, Lundvig D, Petersen C et al (2005) p25α stimulates α-synuclein aggregation and is co-localized with aggregated α-synuclein in α-synucleinopathies. J Biol Chem 280:5703–5715

    Article  PubMed  CAS  Google Scholar 

  181. Bedford L, Hay D, Devoy A et al (2008) Depletion of 26 S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J Neurosci 28:8189–8198

    Article  PubMed  CAS  Google Scholar 

  182. Hashimoto M, Takeda A, Hsu LJ, Takenouchi T, Masliah E (1999) Role of cytochrome c as a stimulator of α-synuclein aggregation in Lewy body disease. J Biol Chem 274:28849–28852

    Article  PubMed  CAS  Google Scholar 

  183. Strauss KM, Martins LM, Plun-Favreau H et al (2005) Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease. Hum Mol Genet 14:2099–2111

    Article  PubMed  CAS  Google Scholar 

  184. Kawamoto Y, Kobayashi Y, Suzuki Y et al (2008) Accumulation of HtrA2/Omi in neuronal and glial inclusions in brains with α-synucleinopathies. J Neuropathol Exp Neurol 67:984–993

    Article  PubMed  Google Scholar 

  185. Lee SS, Kim YM, Junn E et al (2003) Cell cycle aberrations by α-synuclein over-expression and cyclin B immunoreactivity in Lewy bodies. Neurobiol Aging 24:687–696

    Article  PubMed  CAS  Google Scholar 

  186. Jordan-Sciutto KL, Dorsey R, Chalovich EM, Hammond RR, Achim CL (2003) Expression patterns of retinoblastoma protein in Parkinson disease. J Neuropathol Exp Neurol 62:68–74

    PubMed  CAS  Google Scholar 

  187. Arai H, Lee VM, Hill WD, Greenberg BD, Trojanowski JQ (1992) Lewy bodies contain beta-amyloid precursor proteins of Alzheimer’s disease. Brain Res 585:386–390

    Article  PubMed  CAS  Google Scholar 

  188. Yamada T, McGeer PL, Baimbridge KG, McGeer EG (1990) Relative sparing in Parkinson’s disease of substantia nigra dopamine neurons containing calbindin-D28K. Brain Res 526:303–307

    Article  PubMed  CAS  Google Scholar 

  189. Dugger BN, Dickson DW (2010) Cell type specific sequestration of choline acetyltransferase and tyrosine hydroxylase within Lewy bodies. Acta Neuropathol 120:633–639

    Article  PubMed  CAS  Google Scholar 

  190. Nishimura M, Tomimoto H, Suenaga T et al (1994) Synaptophysin and chromogranin A immunoreactivities of Lewy bodies in Parkinson’s disease brains. Brain Res 634:339–344

    Article  PubMed  CAS  Google Scholar 

  191. Huynh DP, Scoles DR, Nguyen D, Pulst SM (2003) The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI. Hum Mol Genet 12:2587–2597

    Article  PubMed  CAS  Google Scholar 

  192. Nakashima S, Ikuta F (1984) Tyrosine hydroxylase protein in Lewy bodies of parkinsonian and senile brains. J Neurol Sci 66:91–96

    Article  PubMed  CAS  Google Scholar 

  193. Yamamoto S, Fukae J, Mori H, Mizuno Y, Hattori N (2006) Positive immunoreactivity for vesicular monoamine transporter 2 in Lewy bodies and Lewy neurites in substantia nigra. Neurosci Lett 396:187–191

    Article  PubMed  CAS  Google Scholar 

  194. Pappolla MA, Andorn AC, Chou SM (1985) Serum protein antigens within Lewy bodies in Parkinson’s disease. Ann Neurol 18: 136 (abstract)

    Google Scholar 

  195. Perry G, Richey P, Siedlak SL, Galloway P, Kawai M, Cras P (1992) Basic fibroblast growth factor binds to filamentous inclusions of neurodegenerative diseases. Brain Res 579:350–352

    Article  PubMed  CAS  Google Scholar 

  196. DeWitt DA, Richey PL, Praprotnik D, Silver J, Perry G (1994) Chondroitin sulfate proteoglycans are a common component of neuronal inclusions and astrocytic reaction in neurodegenerative diseases. Brain Res 656:205–209

    Article  PubMed  CAS  Google Scholar 

  197. Yamada T, McGeer PL, McGeer EG (1992) Lewy bodies in Parkinson’s disease are recognized by antibodies to complement proteins. Acta Neuropathol 84:100–104

    Article  PubMed  CAS  Google Scholar 

  198. Loeffler DA, Camp DM, Conant SB (2006) Complement activation in the Parkinson’s disease substantia nigra: an immunocytochemical study. J Neuroinflammation 3:29–36

    Article  PubMed  CAS  Google Scholar 

  199. Wisniewski T, Haltia M, Ghiso J, Frangione B (1991) Lewy bodies are immunoreactive with antibodies raised to gelsolin related amyloid-Finnish type. Am J Pathol 138:1077–1083

    PubMed  CAS  Google Scholar 

  200. Oláh J, Tokési N, Vincze O 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

    Article  PubMed  CAS  Google Scholar 

  201. Orr CF, Rowe DB, Mizuno Y, Mori H, Halliday GM (2005) A possible role for humoral immunity in the pathogenesis of Parkinson’s disease. Brain 128:2665–2674

    Article  PubMed  Google Scholar 

  202. den Hartog Jager WA (1969) Sphingomyelin in Lewy inclusion bodies in Parkinson’s disease. Arch Neurol 21:615–619

    Article  Google Scholar 

  203. Issidorides MR, Panayotacopoulou MT, Tiniacos G (1990) Similarities between neuronal Lewy bodies in parkinsonism and hepatic Mallory bodies in alcoholism. Pathol Res Pract 186:473–478

    Article  PubMed  CAS  Google Scholar 

  204. Gai WP, Yuan HX, Li XQ, Power JT, Blumbergs PC, Jensen PH (2000) In situ and in vitro study of colocalization and segregation of α-synuclein, ubiquitin, and lipids in Lewy bodies. Exp Neurol 166:324–333

    Article  PubMed  CAS  Google Scholar 

  205. Galloway PG, Perry G (1991) Tropomyosin distinguishes Lewy bodies of Parkinson disease from other neurofibrillary pathology. Brain Res 541:347–349

    Article  PubMed  CAS  Google Scholar 

  206. Leverenz JB, Umar I, Wang Q et al (2007) Proteomic identification of novel proteins in cortical Lewy bodies. Brain Pathol 17:139–145

    Article  PubMed  CAS  Google Scholar 

  207. Whitehouse PJ, Hedreen JC, White CL 3rd, Price DL (1983) Basal forebrain neurons in the dementia of Parkinson disease. Ann Neurol 13:243–248

    Article  PubMed  CAS  Google Scholar 

  208. Wakabayashi K, Kakita A, Hayashi S et al (1998) Apolipoprotein E ε4 allele and progression of cortical Lewy body pathology in Parkinson’s disease. Acta Neuropathol 95:450–454

    Article  PubMed  CAS  Google Scholar 

  209. Mattila PM, Röyttä M, Torikka H, Dickson DW, Rinne JO (1998) Cortical Lewy bodies and Alzheimer-type changes in patients with Parkinson’s disease. Acta Neuropathol 95:576–582

    Article  PubMed  CAS  Google Scholar 

  210. Kövari E, Gold G, Herrmann FR et al (2003) Lewy body densities in the entorhinal and anterior cingulate cortex predict cognitive deficits in Parkinson’s disease. Acta Neuropathol 106:83–88

    PubMed  Google Scholar 

  211. Terry RD (2000) Do neuronal inclusions kill the cell? J Neural Transm 59 (Suppl.): 91-93

    Google Scholar 

  212. Lashuel HA, Petre BM, Wall J et al (2002) α-Synuclein, especially the Parkinson’s disease-associated mutants, forms pore-like annular and tubular protofibrils. J Mol Biol 322:1089–1102

    Article  PubMed  CAS  Google Scholar 

  213. Ding TT, Lee SJ, Rochet JC, Lansbury PT Jr (2002) Annular α-synuclein protofibrils are produced when spherical protofibrils are incubated in solution or bound to brain-derived membranes. Biochemistry 41:10209–10217

    Article  PubMed  CAS  Google Scholar 

  214. Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT Jr (2002) Amyloid pores from pathogenic mutations. Nature 418:291

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  216. Sawada H, Kohno R, Kihara T et al (2004) Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes α-synuclein inclusions. J Biol Chem 279:10710–10719

    Article  PubMed  CAS  Google Scholar 

  217. Olanow CW, Perl DP, DeMartino GN, McNaught KS (2004) Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol 3:496–503

    Article  PubMed  Google Scholar 

  218. Tanaka M, Kim YM, Lee G et al (2004) Aggresomes formed by α-synuclein and synphilin-1 are cytoprotective. J Biol Chem 279:4625–4631

    Article  PubMed  CAS  Google Scholar 

  219. Pan T, Kondo S, Le W, Jankovic J (2008) The role of autophagy–lysosome pathway in neurodegeneration associated with Parkinson’s disease. Brain 131:1969–1978

    Article  PubMed  Google Scholar 

  220. Pandey UB, Nie Z, Batlevi Y et al (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447:859–863

    Article  PubMed  CAS  Google Scholar 

  221. Johansen T, Lamark T (2011) Selective autophagy mediated by autophagic adapter proteins. Autophagy 7:279–296

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  223. Takeda A, Mallory M, Sundsmo M, Honer W, Hansen L, Masliah E (1998) Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. Am J Pathol 152:367–372

    PubMed  CAS  Google Scholar 

  224. Takeda A, Hashimoto M, Mallory M, Sundsumo M, Hansen L, Masliah E (2000) C-terminal alpha-synuclein immunoreactivity in structures other than Lewy bodies in neurodegenerative disorders. Acta Neuropathol 99:296–304

    Article  PubMed  CAS  Google Scholar 

  225. Tanji K, Mori F, Mimura J et al (2010) Proteinase K-resistant α-synuclein is deposited in presynapses in human Lewy body disease and A53T α-synuclein transgenic mice. Acta Neuropathol 120:145–154

    Article  PubMed  CAS  Google Scholar 

  226. Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K (2011) Synphilin-1 binding protein, NUB1, is colocalized with non-fibrillar, proteinase K-resistant α-synuclein to presynapses in Lewy body disease. J Neuropathol Exp Neurol 70:879–889

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (K.W., K.T., F.M.), a Grant for Hirosaki University Institutional Research (K.W.), the Collaborative Research Project (2011–2209) of the Brain Research Institute, Niigata University (F.M.), Grants-in Aid from the Research Committee for Ataxic Disease, the Ministry of Health, Labour and Welfare, Japan (K.W.), and the Intramural Research Grant (21B-4) for Neurological and Psychiatric Disorders of NCNP (K.W.). The authors wish to express their gratitude to M. Nakata for her technical assistance.

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  1. Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan

    Koichi Wakabayashi, Kunikazu Tanji, Saori Odagiri, Yasuo Miki & Fumiaki Mori

  2. Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan

    Hitoshi Takahashi

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  1. Koichi Wakabayashi
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Correspondence to Koichi Wakabayashi.

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Wakabayashi, K., Tanji, K., Odagiri, S. et al. The Lewy Body in Parkinson’s Disease and Related Neurodegenerative Disorders. Mol Neurobiol 47, 495–508 (2013). https://doi.org/10.1007/s12035-012-8280-y

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