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Published in: Acta Neuropathologica 4/2004

01-04-2004 | Regular Paper

Accumulation of phosphorylated α-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy

Authors: Makoto Nishie, Fumiaki Mori, Hideo Fujiwara, Masato Hasegawa, Makoto Yoshimoto, Takeshi Iwatsubo, Hitoshi Takahashi, Koichi Wakabayashi

Published in: Acta Neuropathologica | Issue 4/2004

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Abstract

We immunohistochemically examined the brain and peripheral sympathetic ganglia from eight patients with multiple system atrophy (MSA), using an antibody specific for phosphorylated α-synuclein (anti-PSer129). Phosphorylated α-synuclein was deposited in five cellular locations: oligodendroglial cytoplasm and nucleus, and neuronal cytoplasm, processes and nucleus. Many neuronal cytoplasmic inclusions (NCIs) were found in the pontine and inferior olivary nuclei and, to a lesser extent, in the substantia nigra, locus ceruleus, and neocortical and hippocampal neurons. NCIs were also found in the sympathetic ganglia in two out of the eight cases. Moreover, anti-PSer129 immunohistochemistry revealed extensive neuropil pathology; swollen neurites were abundant in the pontine nucleus, delicate neurites were observed in the deeper layers of the cerebral cortex and thalamus, and neuropil threads and dot-like structures were distributed in the basal ganglia and brainstem. Diffuse neuronal cytoplasmic staining (pre-NCI) was frequently found in the pontine and inferior olivary nuclei. Thus, the widespread accumulation of phosphorylated α-synuclein in both glial and neuronal cells is a pathological feature in patients suffering from MSA.
Literature
1.
go back to reference Bannister R, Oppenheimer DR (1972) Degenerative diseases of the nervous system associated with autonomic failure. Brain 95:457–474PubMed Bannister R, Oppenheimer DR (1972) Degenerative diseases of the nervous system associated with autonomic failure. Brain 95:457–474PubMed
2.
go back to reference Duda JE, Lee VM, Trojanowski JQ (2000) Neuropathology of synuclein aggregates. J Neurosci Res 61:121–127CrossRefPubMed Duda JE, Lee VM, Trojanowski JQ (2000) Neuropathology of synuclein aggregates. J Neurosci Res 61:121–127CrossRefPubMed
3.
go back to reference Forman MS, Schmidt ML, Kasturi S, Perl DP, Lee VM-Y, Trojanowski JQ (2002) Tau and α-synuclein pathology in amygdala of parkinsonism-dementia complex patients of Guam. Am J Pathol 160:1725–1731PubMed Forman MS, Schmidt ML, Kasturi S, Perl DP, Lee VM-Y, Trojanowski JQ (2002) Tau and α-synuclein pathology in amygdala of parkinsonism-dementia complex patients of Guam. Am J Pathol 160:1725–1731PubMed
4.
go back to reference Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg S, Shen J, Takio K, Iwatsubo T (2002) α-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164 Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg S, Shen J, Takio K, Iwatsubo T (2002) α-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164
5.
go back to reference Gray F, Vincent D, Hauw JJ (1988) Quantitative study of lateral horn cells in 15 cases of multiple system atrophy. Acta Neuropathol (Berl) 75:513–518 Gray F, Vincent D, Hauw JJ (1988) Quantitative study of lateral horn cells in 15 cases of multiple system atrophy. Acta Neuropathol (Berl) 75:513–518
6.
go back to reference Hamilton RL (2000) Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using α-synuclein immunohistochemistry. Brain Pathol 10:378–384PubMed Hamilton RL (2000) Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using α-synuclein immunohistochemistry. Brain Pathol 10:378–384PubMed
7.
go back to reference Hasegawa M, Fujiwara H, Nonaka T, Wakabayashi K, Takahashi H, Lee VM-Y, Trojanowski JQ, Mann D, Iwatsubo T (2002) Phosphorylated α-synuclein is ubiquitinated in α-synucleinopathy lesions. J Biol Chem 277:49071–49076CrossRefPubMed Hasegawa M, Fujiwara H, Nonaka T, Wakabayashi K, Takahashi H, Lee VM-Y, Trojanowski JQ, Mann D, Iwatsubo T (2002) Phosphorylated α-synuclein is ubiquitinated in α-synucleinopathy lesions. J Biol Chem 277:49071–49076CrossRefPubMed
8.
go back to reference Hishikawa N, Hashizume Y, Yoshida M, Hirayama M, Sobue G (2002) Neuropathology of pure autonomic failure. Neurol Med (Tokyo) 57:35–43 Hishikawa N, Hashizume Y, Yoshida M, Hirayama M, Sobue G (2002) Neuropathology of pure autonomic failure. Neurol Med (Tokyo) 57:35–43
9.
go back to reference Hishikawa N, Hashizume Y, Ujihara N, Okada Y, Yoshida M, Sobue G (2003) α-Synuclein-positive structures in association with diffuse neurofibrillary tangles with calcification. Neuropathol Appl Neurobiol 29:280–287CrossRefPubMed Hishikawa N, Hashizume Y, Ujihara N, Okada Y, Yoshida M, Sobue G (2003) α-Synuclein-positive structures in association with diffuse neurofibrillary tangles with calcification. Neuropathol Appl Neurobiol 29:280–287CrossRefPubMed
10.
go back to reference Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, Rohan de Silva HA, Kittel A, Saitoh T (1995) The precursor protein of non-Aβ component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 14:467–475PubMed Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, Rohan de Silva HA, Kittel A, Saitoh T (1995) The precursor protein of non-Aβ component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 14:467–475PubMed
11.
go back to reference Jellinger KA (2003) α-Synuclein pathology in Parkinson’s and Alzheimer’s disease brain: incidence and topographic distribution—a pilot study. Acta Neuropathol 106:191–201CrossRefPubMed Jellinger KA (2003) α-Synuclein pathology in Parkinson’s and Alzheimer’s disease brain: incidence and topographic distribution—a pilot study. Acta Neuropathol 106:191–201CrossRefPubMed
12.
go back to reference Kahle PJ, Neumann M, Ozmen L, Müller V, Jacobsen H, Spooren W, Fuss B, Mallon B, Macklin WB, Fujiwara H, Hasegawa M, Iwatsubo T, Kretzschmar HA, Haass C (2002) Hyperphosphorylation and insolubility of α-synuclein in transgenic mouse oligodendrocytes. EMBO Rep 3:583–588CrossRefPubMed Kahle PJ, Neumann M, Ozmen L, Müller V, Jacobsen H, Spooren W, Fuss B, Mallon B, Macklin WB, Fujiwara H, Hasegawa M, Iwatsubo T, Kretzschmar HA, Haass C (2002) Hyperphosphorylation and insolubility of α-synuclein in transgenic mouse oligodendrocytes. EMBO Rep 3:583–588CrossRefPubMed
13.
go back to reference Kennedy PGE, Duchen LW (1985) A quantitative study of intermediolateral column cells in motor neuron disease and the Shy-Drager syndrome. J Neurol Neurosurg Psychiatry 48:1103–1106PubMed Kennedy PGE, Duchen LW (1985) A quantitative study of intermediolateral column cells in motor neuron disease and the Shy-Drager syndrome. J Neurol Neurosurg Psychiatry 48:1103–1106PubMed
14.
go back to reference Konno H, Yamamoto T, Iwasaki Y, Iizuka H (1986) Shy-Drager syndrome and amyotrophic lateral sclerosis. Cytoarchitectonic and morphometric studies of sacral autonomic neurons. J Neurol Sci 73:193–204CrossRefPubMed Konno H, Yamamoto T, Iwasaki Y, Iizuka H (1986) Shy-Drager syndrome and amyotrophic lateral sclerosis. Cytoarchitectonic and morphometric studies of sacral autonomic neurons. J Neurol Sci 73:193–204CrossRefPubMed
15.
go back to reference Lippa CF, Fujiwara H, Mann DMA, Giasson B, Baba M, Schmidt ML, Nee LE, O’Connell B, Pollen DA, St. George-Hyslop P, Ghetti B, Nochlin D, Bird TD, Cairns NJ, Lee VM-Y, Iwatsubo T, Trojanowski JQ (1998) Lewy bodies contain altered α-synuclein in brains of many familial Alzheimer’s disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol 153:1365–1370PubMed Lippa CF, Fujiwara H, Mann DMA, Giasson B, Baba M, Schmidt ML, Nee LE, O’Connell B, Pollen DA, St. George-Hyslop P, Ghetti B, Nochlin D, Bird TD, Cairns NJ, Lee VM-Y, Iwatsubo T, Trojanowski JQ (1998) Lewy bodies contain altered α-synuclein in brains of many familial Alzheimer’s disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol 153:1365–1370PubMed
16.
go back to reference Lippa CF, Schmidt M, Lee VM, Trojanowski JQ (1999) Antibodies to α-synuclein detect Lewy bodies in many Down’s syndrome brains with Alzheimer’s disease. Ann Neurol 45:353–357PubMed Lippa CF, Schmidt M, Lee VM, Trojanowski JQ (1999) Antibodies to α-synuclein detect Lewy bodies in many Down’s syndrome brains with Alzheimer’s disease. Ann Neurol 45:353–357PubMed
17.
go back to reference Marouteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8:2804–2815PubMed Marouteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8:2804–2815PubMed
18.
go back to reference Mori F, Inenaga C, Yoshimoto M, Umezu H, Tanaka R, Takahashi H, Wakabayashi K (2002) α-Synuclein immunoreactivity in normal and neoplastic Schwann cells. Acta Neuropathol 103:145–151PubMed Mori F, Inenaga C, Yoshimoto M, Umezu H, Tanaka R, Takahashi H, Wakabayashi K (2002) α-Synuclein immunoreactivity in normal and neoplastic Schwann cells. Acta Neuropathol 103:145–151PubMed
19.
go back to reference Mori F, Tanji K, Yoshimoto M, Takahashi H, Wakabayashi K (2002) Demonstration of α-synuclein immunoreactivity in neuronal and glial cytoplasm in normal human brain tissue using proteinase K and fromic acid pretreatment. Exp Neurol 176:98–104CrossRefPubMed Mori F, Tanji K, Yoshimoto M, Takahashi H, Wakabayashi K (2002) Demonstration of α-synuclein immunoreactivity in neuronal and glial cytoplasm in normal human brain tissue using proteinase K and fromic acid pretreatment. Exp Neurol 176:98–104CrossRefPubMed
20.
go back to reference Neumann M, Kahle PJ, Giasson BI, Ozmen L, Borroni E, Spooren W, Müller V, Odoy S, Fujiwara H, Hasegawa M, Iwatsubo T, Trojanowski JQ, Kretzschmar HA, Haass C (2002) Misfolded proteinase K-resistant hyperphosphorylated α-synuclein in aged transgenic mice with locomotor deterioration and in human α-synucleinopathies. J Clin Invest 110:1429–1439CrossRefPubMed Neumann M, Kahle PJ, Giasson BI, Ozmen L, Borroni E, Spooren W, Müller V, Odoy S, Fujiwara H, Hasegawa M, Iwatsubo T, Trojanowski JQ, Kretzschmar HA, Haass C (2002) Misfolded proteinase K-resistant hyperphosphorylated α-synuclein in aged transgenic mice with locomotor deterioration and in human α-synucleinopathies. J Clin Invest 110:1429–1439CrossRefPubMed
21.
go back to reference Okochi M, Walter J, Koyama A, Nakajo S, Baba M, Iwatsubo T, Meijer L, Kahle PJ, Haass C (2000) Constitutive phosphorylation of the Parkinson’s disease associated α-synuclein. J Biol Chem 275:390–397CrossRefPubMed Okochi M, Walter J, Koyama A, Nakajo S, Baba M, Iwatsubo T, Meijer L, Kahle PJ, Haass C (2000) Constitutive phosphorylation of the Parkinson’s disease associated α-synuclein. J Biol Chem 275:390–397CrossRefPubMed
22.
go back to reference Papp MI, Kahn JE, Lantos PL (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 94:79–100PubMed Papp MI, Kahn JE, Lantos PL (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 94:79–100PubMed
23.
go back to reference Parkkinen L, Soininen H, Alafuzoff I (2003) Regional distribution of α-synuclein pathology in unimpaired aging and Alzheimer disease. J Neuropathol Exp Neurol 62:363–367 Parkkinen L, Soininen H, Alafuzoff I (2003) Regional distribution of α-synuclein pathology in unimpaired aging and Alzheimer disease. J Neuropathol Exp Neurol 62:363–367
24.
go back to reference Piao Y-S, Mori F, Hayashi S, Tanji K, Yoshimoto M, Kakita A, Wakabayashi K, Takahashi H (2003) α-Synuclein pathology affecting Bergmann glia of the cerebellum in patients with α-synucleinopathies. Acta Neuropathol 105:403–409PubMed Piao Y-S, Mori F, Hayashi S, Tanji K, Yoshimoto M, Kakita A, Wakabayashi K, Takahashi H (2003) α-Synuclein pathology affecting Bergmann glia of the cerebellum in patients with α-synucleinopathies. Acta Neuropathol 105:403–409PubMed
25.
go back to reference Richter-Landsberg C, Gorath M, Trojanowski JQ, Lee VM-Y (2000) α-Synuclein is developmentally expressed in cultured rat brain oligodendrocytes. J Neurosci Res 62:9–14PubMed Richter-Landsberg C, Gorath M, Trojanowski JQ, Lee VM-Y (2000) α-Synuclein is developmentally expressed in cultured rat brain oligodendrocytes. J Neurosci Res 62:9–14PubMed
26.
go back to reference Saito Y, Kawashima A, Ruberu NN, Fujiwara H, Koyama S, Sawabe M, Arai T, Nagura H, Yamanouchi H, Hasegawa M, Iwatsubo T, Murayama S (2003) Accumulation of phosphorylated α-synuclein in aging human brain. J Neuropathol Exp Neurol 62:644–654PubMed Saito Y, Kawashima A, Ruberu NN, Fujiwara H, Koyama S, Sawabe M, Arai T, Nagura H, Yamanouchi H, Hasegawa M, Iwatsubo T, Murayama S (2003) Accumulation of phosphorylated α-synuclein in aging human brain. J Neuropathol Exp Neurol 62:644–654PubMed
27.
go back to reference Sampathu DM, Giasson BI, Pawlyk AC, Trojanowski JQ, Lee VM-Y (2003) Ubiquitination of α-synuclein is not required for formation of pathological inclusions in α-synucleinopathies. Am J Pathol 163:91–100PubMed Sampathu DM, Giasson BI, Pawlyk AC, Trojanowski JQ, Lee VM-Y (2003) Ubiquitination of α-synuclein is not required for formation of pathological inclusions in α-synucleinopathies. Am J Pathol 163:91–100PubMed
28.
go back to reference Takahashi M, Kanuka H, Fujiwara H, Koyama A, Hasegawa M, Miura M, Iwatsubo T (2003) Phosphorylation of α-synuclein characteristic of synucleinopathy lesions is recapitulated in α-synuclein transgenic Dorosophilia. Neurosci Lett 336:155–158CrossRefPubMed Takahashi M, Kanuka H, Fujiwara H, Koyama A, Hasegawa M, Miura M, Iwatsubo T (2003) Phosphorylation of α-synuclein characteristic of synucleinopathy lesions is recapitulated in α-synuclein transgenic Dorosophilia. Neurosci Lett 336:155–158CrossRefPubMed
29.
go back to reference Tanji K, Imaizumi T, Yoshida H, Mori F, Yoshimoto M, Satoh K, Wakabayashi K (2001) Expression of α-synuclein in a human glioma cell line and its up-regulation by interleukin-1β. Neuroreport 12:1909–1912PubMed Tanji K, Imaizumi T, Yoshida H, Mori F, Yoshimoto M, Satoh K, Wakabayashi K (2001) Expression of α-synuclein in a human glioma cell line and its up-regulation by interleukin-1β. Neuroreport 12:1909–1912PubMed
30.
go back to reference Tu PH, Galvin JE, Baba M, Giasson B, Tomita T, Leight S, Nakajo S, Iwatsubo T, Trojanowski JQ, Lee VM (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α-synuclein. Ann Neurol 44:415–422PubMed Tu PH, Galvin JE, Baba M, Giasson B, Tomita T, Leight S, Nakajo S, Iwatsubo T, Trojanowski JQ, Lee VM (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α-synuclein. Ann Neurol 44:415–422PubMed
31.
go back to reference Wakabayashi K, Hayashi S, Kakita A, Yamada M, Toyoshima Y, Yoshimoto M, Takahashi H (1998) Accumulation of α-synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy. Acta Neuropathol 96:445–452CrossRefPubMed Wakabayashi K, Hayashi S, Kakita A, Yamada M, Toyoshima Y, Yoshimoto M, Takahashi H (1998) Accumulation of α-synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy. Acta Neuropathol 96:445–452CrossRefPubMed
32.
go back to reference Wakabayashi K, Yoshimoto M, Fukushima T, Koide R, Horikawa Y, Morita T, Takahashi H (1999) Widespread occurrence of α-synuclein/NACP-immunoreactive neuronal inclusions in juvenile and adult-onset Hallervorden-Spatz disease with Lewy bodies. Neuropathol Appl Neurobiol 25:363–368PubMed Wakabayashi K, Yoshimoto M, Fukushima T, Koide R, Horikawa Y, Morita T, Takahashi H (1999) Widespread occurrence of α-synuclein/NACP-immunoreactive neuronal inclusions in juvenile and adult-onset Hallervorden-Spatz disease with Lewy bodies. Neuropathol Appl Neurobiol 25:363–368PubMed
33.
go back to reference Wenning GK, Shlomo YB, Magalhaes M, Daniel SE, Quinn NP (1994) Clinical features and natural history of multiple system atrophy: an analysis of 100 cases. Brain 117:835–845PubMed Wenning GK, Shlomo YB, Magalhaes M, Daniel SE, Quinn NP (1994) Clinical features and natural history of multiple system atrophy: an analysis of 100 cases. Brain 117:835–845PubMed
34.
go back to reference Yamazaki M, Arai Y, Baba M, Iwatsubo T, Mori O, Katayama Y, Oyanagi K (2000) α-Synuclein inclusions in amygdala in the brains of patients with the parkinsonism-dementia complex of Guam. J Neuropathol Exp Neurol 59:585–591PubMed Yamazaki M, Arai Y, Baba M, Iwatsubo T, Mori O, Katayama Y, Oyanagi K (2000) α-Synuclein inclusions in amygdala in the brains of patients with the parkinsonism-dementia complex of Guam. J Neuropathol Exp Neurol 59:585–591PubMed
35.
go back to reference Yokota O, Terada S, Ishizu H, Tsuchiya K, Kitamura Y, Ikeda K, Ueda K, Kuroda S (2002) NACP/α-synuclein immunoreactivity in diffuse neurofibrillary tangles with calcification (DNCT). Acta Neuropathol 104:333–341PubMed Yokota O, Terada S, Ishizu H, Tsuchiya K, Kitamura Y, Ikeda K, Ueda K, Kuroda S (2002) NACP/α-synuclein immunoreactivity in diffuse neurofibrillary tangles with calcification (DNCT). Acta Neuropathol 104:333–341PubMed
Metadata
Title
Accumulation of phosphorylated α-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy
Authors
Makoto Nishie
Fumiaki Mori
Hideo Fujiwara
Masato Hasegawa
Makoto Yoshimoto
Takeshi Iwatsubo
Hitoshi Takahashi
Koichi Wakabayashi
Publication date
01-04-2004
Publisher
Springer-Verlag
Published in
Acta Neuropathologica / Issue 4/2004
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-003-0811-1

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