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.
Similar content being viewed by others
References
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
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
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
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
Singleton AB, Farrer M, Johnson J et al (2003) α-Synuclein locus triplication causes Parkinson’s disease. Science 302:841
Spillantini MG, Schmidt ML, Lee VM-Y, Trojanowski JQ, Jakes R, Goedert M (1997) α-Synuclein in Lewy bodies. Nature 388:839–840
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
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
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
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
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
Wong K, Sidransky E, Verma A et al (2004) Neuropathology provides clue to the pathophysiology of Gaucher disease. Mol Genet Metab 82:192–207
Hamilton R (2000) Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using α-synuclein immunohistochemistry. Brain Pathol 10:378–384
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
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
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
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
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
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
Lewy FH (1912) Paralysis agitans. I. Pathologische Anatomie. In: Lewandowsky M (ed) Hundbuch der Neurologie III. Springer, Berlin, pp 920–933
Tretiakoff MC (1919) Contribution a l’étude de l’anatomie pathologique de Locus Niger de Soemmerling. Université de Paris.
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
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
Kosaka K (1978) Lewy bodies in cerebral cortex. Report of three cases. Acta Neuropathol 42:127–134
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
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
Fujiwara H, Hasegawa M, Dohmae N et al (2002) α-Synuclein is phosphorylated in synucleinopathy lesions. Nature Cell Biol 4:160–164
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
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
Wakabayashi K, Takahashi H (1996) Gallyas-positive, tau-negative glial inclusions in Parkinson’s disease midbrain. Neurosci Lett 217:133–136
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
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
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
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
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
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
Langston JW, Forno LS (1978) The hypothalamus in Parkinson disease. Ann Neurol 3:129–133
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
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
Ohama E, Ikuta F (1976) Parkinson’s disease. Distribution of Lewy bodies and monoamine neurons system. Acta Neuropathol 34:311–319
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
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
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
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
Wakabayashi K, Takahashi H (1997) The intermediolateral nucleus and Clarke’s column in Parkinson’s disease. Acta Neuropathol 94:287–289
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
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
Braak H, Braak E, Yilmazer D et al (1994) Amygdala pathology in Parkinson’s disease. Acta Neuropathol 88:493–500
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
Forno LS, Norville RL (1976) Ultrastructure of Lewy bodies in the stellate ganglion. Acta Neuropathol 34:183–197
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
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
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
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
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
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
Wakabayashi K, Takahashi H (1997) Neuropathology of autonomic nervous system in Parkinson’s disease. Eur Neurol 38(Suppl 2):2–7
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
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
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
Ikemura M, Saito Y, Sengoku R et al (2008) Lewy body pathology involves cutaneous nerves. J Neuropathol Exp Neurol 67:945–953
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
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
Langston JW (2006) The Parkinson’s complex: Parkinsonism is just the tip of the iceberg. Ann Neurol 59:591–596
Lim SY, Fox SH, Lang AE (2009) Overview of the extranigral aspects of Parkinson disease. Arch Neurol 66:167–172
Ross GW, Abbott RD, Petrovitch H et al (2006) Association of olfactory dysfunction with incidental Lewy bodies. Mov Disord 21:2062–2067
Abbott RD, Ross GW, Petrovitch H et al (2007) Bowel movement frequency in late-life and incidental Lewy bodies. Mov Disord 22:1581–1586
Beach TG, Adler CH, Sue LI et al (2008) Reduced striatal tyrosine hydroxylase in incidental Lewy body disease. Acta Neuropathol 115:445–451
DelleDonne A, Klos J, Fujishiro H et al (2008) Incidental Lewy body disease and preclinical Parkinson’s disease. Arch Neurol 65:1074–1080
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
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
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
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
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
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
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
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
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
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
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
Jellinger KA (2008) A critical reappraisal of current staging of Lewy-related pathology in human brain. Acta Neuropathol 116:1–16
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
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
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
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
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
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
Gibb WR, Scott T, Lees AJ (1991) Neuronal inclusions of Parkinson’s disease. Mov Disord 6:2–11
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
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
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
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
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
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
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
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
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
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
Goldman JE, Yen SH, Chiu FC, Peress NS (1983) Lewy bodies of Parkinson’s disease contain neurofilament antigens. Science 221:1082–1084
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
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
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
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
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
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
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
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
Bandopadhyay R, Kingsbury AE, Muqit MM et al (2005) Synphilin-1 and parkin show overlap** expression patterns in human brain and form aggresomes in response to proteasomal inhibition. Neurobiol Dis 20:401–411
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
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
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
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
Nagao M, Hayashi H (2009) Glycogen synthase kinase-3beta is associated with Parkinson’s disease. Neurosci Lett 449:103–107
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
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
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
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
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
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
McNaught KS, Shashidharan P, Perl DP, Jenner P, Olanow CW (2002) Aggresome-related biogenesis of Lewy bodies. Eur J Neurosci 16:2136–2148
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
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
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
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
Lindersson E, Beedholm R, Hojrup P et al (2004) Proteasomal inhibition by α-synuclein filaments and oligomers. J Biol Chem 279:12924–12934
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
Takahashi-Fujigasaki J, Fujigasaki H (2006) Histone deacetylase (HDAC) 4 involvement in both Lewy and Marinesco bodies. J Neuropathol Appl Neurobiol 32:562–566
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
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
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
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
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
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
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
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
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
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
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)
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
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
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
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
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
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
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
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
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
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
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
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
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
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
** 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
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
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
Schipper HM, Liberman A, Stopa EG (1998) Neural heme oxygenase-1 expression in idiopathic Parkinson’s disease. Exp Neurol 150:60–68
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
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
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
Iwatsubo T, Nakano I, Fukunaga K, Miyamoto E (1991) Ca2+/calmodulin-dependent protein kinase II immunoreactivity in Lewy bodies. Acta Neuropathol 82:159–163
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
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
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
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
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
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
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
Zhu X, Siedlak SL, Smith MA, Perry G, Chen SG (2006) LRRK2 protein is a component of Lewy bodies. Ann Neurol 60:617–618
Zhu X, Babar A, Siedlak SL et al (2006) LRRK2 in Parkinson’s disease and dementia with Lewy bodies. Mol Neurodegener 1:17–25
Gandhi S, Muqit MM, Stanyer L et al (2006) PINK1 protein in normal human brain and Parkinson’s disease. Brain 129:1720–1731
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Dugger BN, Dickson DW (2010) Cell type specific sequestration of choline acetyltransferase and tyrosine hydroxylase within Lewy bodies. Acta Neuropathol 120:633–639
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
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
Nakashima S, Ikuta F (1984) Tyrosine hydroxylase protein in Lewy bodies of parkinsonian and senile brains. J Neurol Sci 66:91–96
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
Pappolla MA, Andorn AC, Chou SM (1985) Serum protein antigens within Lewy bodies in Parkinson’s disease. Ann Neurol 18: 136 (abstract)
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
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
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
Loeffler DA, Camp DM, Conant SB (2006) Complement activation in the Parkinson’s disease substantia nigra: an immunocytochemical study. J Neuroinflammation 3:29–36
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
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
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
den Hartog Jager WA (1969) Sphingomyelin in Lewy inclusion bodies in Parkinson’s disease. Arch Neurol 21:615–619
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
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
Galloway PG, Perry G (1991) Tropomyosin distinguishes Lewy bodies of Parkinson disease from other neurofibrillary pathology. Brain Res 541:347–349
Leverenz JB, Umar I, Wang Q et al (2007) Proteomic identification of novel proteins in cortical Lewy bodies. Brain Pathol 17:139–145
Whitehouse PJ, Hedreen JC, White CL 3rd, Price DL (1983) Basal forebrain neurons in the dementia of Parkinson disease. Ann Neurol 13:243–248
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
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
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
Terry RD (2000) Do neuronal inclusions kill the cell? J Neural Transm 59 (Suppl.): 91-93
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
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
Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT Jr (2002) Amyloid pores from pathogenic mutations. Nature 418:291
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
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
Olanow CW, Perl DP, DeMartino GN, McNaught KS (2004) Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol 3:496–503
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
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
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
Johansen T, Lamark T (2011) Selective autophagy mediated by autophagic adapter proteins. Autophagy 7:279–296
Sidhu A, Wersinger C, Vernier P (2004) Does α-synuclein modulate dopaminergic synaptic content and tone at the synapse? FASEB J 18:637–647
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
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
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
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
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-012-8280-y