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Published in: Acta Neuropathologica 5/2007

01-05-2007 | Original Paper

TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation

Published in: Acta Neuropathologica | Issue 5/2007

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Abstract

Recently, 43-kDa TAR DNA-binding protein (TDP-43) was identified as a component of ubiquitinated inclusions (UIs) in sporadic amyotrophic lateral sclerosis (SALS). To clarify whether TDP-43 immunoreactivity is present in neuronal inclusions in familial ALS (FALS), we examined immunohistochemically the brains and spinal cords from four cases of FALS, two with Cu/Zn superoxide dismutase (SOD1) gene mutation and two without, together with three cases of SALS and three control subjects, using two antibodies, one polyclonal and one monoclonal, against TDP-43. Neuropathologically, the SOD1-related FALS cases were characterized by Lewy body-like hyaline inclusions (LBHIs) in the lower motor neurons. On the other hand, the SOD1-unrelated FALS cases showed degeneration restricted to the upper and lower motor neuron systems, with Bunina bodies (BBs) and UIs in the lower motor neurons, being indistinguishable from SALS. No cytoplasmic TDP-43 immunoreactivity was observed in the control subjects or SOD1-related FALS cases; LBHIs were ubiquitinated, but negative for TDP-43. UIs observed in the SALS and SOD1-unrelated FALS cases were clearly positive for TDP-43. BBs were negative for this protein. Interestingly, in these SALS and FALS cases, glial cells were also found to have cytoplasmic TDP-43-positive inclusions. These findings indicate that the histological and molecular pathology of SALS can occur as a phenotype of FALS without SOD1 mutation.
Literature
1.
go back to reference Arai A, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T (2006) TDP-43 is a component of ubiquitin-positive inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611PubMedCrossRef Arai A, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T (2006) TDP-43 is a component of ubiquitin-positive inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611PubMedCrossRef
2.
go back to reference Davidson Y, Kelley T, Mackenzie IRA, Pickering-Brown S, Du Plessis D, Neary D, Snowden JS, Mann DMA (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol. doi:10.1007/s00401-006-0189-y Davidson Y, Kelley T, Mackenzie IRA, Pickering-Brown S, Du Plessis D, Neary D, Snowden JS, Mann DMA (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol. doi:10.​1007/​s00401-006-0189-y
3.
go back to reference Deng H-X, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung WY, Getzoff ED, Hu P, Herzfeldt B, Roos RP, Warner C, Deng G, Soiano E, Smyth C, Parge HE, Ahmed A, Roses AD, Hallewell RA, Pericak-Vance MA, Siddique T (1993) Amyotrophic lateral sclerosis and structural defects in Cu/Zn superoxide dismutase. Science 261:1047–1051PubMedCrossRef Deng H-X, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung WY, Getzoff ED, Hu P, Herzfeldt B, Roos RP, Warner C, Deng G, Soiano E, Smyth C, Parge HE, Ahmed A, Roses AD, Hallewell RA, Pericak-Vance MA, Siddique T (1993) Amyotrophic lateral sclerosis and structural defects in Cu/Zn superoxide dismutase. Science 261:1047–1051PubMedCrossRef
4.
go back to reference Engel WK, Kurland LT, Klatzo I (1959) An inherited disease similar to amyotrophic lateral sclerosis with a pattern of posterior column involvement. An intermediate form? Brain 82:203–220PubMedCrossRef Engel WK, Kurland LT, Klatzo I (1959) An inherited disease similar to amyotrophic lateral sclerosis with a pattern of posterior column involvement. An intermediate form? Brain 82:203–220PubMedCrossRef
5.
go back to reference Hirano A, Kurland LT, Sayre GP (1967) Familial amyotrophic lateral sclerosis. A subgroup characterized by posterior and spinocerebellar tract involvement and hyaline inclusions in the anterior horn cells. Arch Neurol 16:232–243PubMed Hirano A, Kurland LT, Sayre GP (1967) Familial amyotrophic lateral sclerosis. A subgroup characterized by posterior and spinocerebellar tract involvement and hyaline inclusions in the anterior horn cells. Arch Neurol 16:232–243PubMed
6.
go back to reference Horton WA, Eldridge R, Brody JA (1976) Familial motor neuron disease. Evidence for at least three different types. Neurology 26:460–465PubMed Horton WA, Eldridge R, Brody JA (1976) Familial motor neuron disease. Evidence for at least three different types. Neurology 26:460–465PubMed
7.
go back to reference Leigh PN, Anderton BH, Dodson A, Gallo J-M, Swash M, Power DM (1988) Ubiquitin deposits in anterior horn cells in motor neuron disease. Neurosci Lett 93:197–203PubMedCrossRef Leigh PN, Anderton BH, Dodson A, Gallo J-M, Swash M, Power DM (1988) Ubiquitin deposits in anterior horn cells in motor neuron disease. Neurosci Lett 93:197–203PubMedCrossRef
8.
go back to reference Leigh PN, Withwell H, Garofalo O, Buller J, Swash M, Martin JE, Gallo J-M, Weller RO, Anerton BH (1991) Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis. Morphology, distribution, and specificity. Brain 114:775–788PubMedCrossRef Leigh PN, Withwell H, Garofalo O, Buller J, Swash M, Martin JE, Gallo J-M, Weller RO, Anerton BH (1991) Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis. Morphology, distribution, and specificity. Brain 114:775–788PubMedCrossRef
9.
go back to reference Lowe J, Lennox G, Jefferson D, Morrell K, McQuire D, Gray T, Landon M, Doherty FJ, Mayer RI (1988) A filamentous inclusion body within anterior horn neurons in motor neuron disease defined by immunocytochemical localization of ubiquitin. Neurosci Lett 94:203–210PubMedCrossRef Lowe J, Lennox G, Jefferson D, Morrell K, McQuire D, Gray T, Landon M, Doherty FJ, Mayer RI (1988) A filamentous inclusion body within anterior horn neurons in motor neuron disease defined by immunocytochemical localization of ubiquitin. Neurosci Lett 94:203–210PubMedCrossRef
10.
go back to reference Mizuno Y, Amari M, Takatama M, Aizawa H, Mihara B, Okamoto K (2006) Transferrin localizes in Bunina bodies in amyotrophic lateral sclerosis. Acta Neuropathol 112:597–603PubMedCrossRef Mizuno Y, Amari M, Takatama M, Aizawa H, Mihara B, Okamoto K (2006) Transferrin localizes in Bunina bodies in amyotrophic lateral sclerosis. Acta Neuropathol 112:597–603PubMedCrossRef
11.
go back to reference Mizusawa H, Hirano A, Yen S-H (1991) Anterior horn cell inclusions in familial amyotrophic lateral sclerosis contain ubiquitin and phosphorylated neurofilaments epitopes. Neuropathology 11:11–20 Mizusawa H, Hirano A, Yen S-H (1991) Anterior horn cell inclusions in familial amyotrophic lateral sclerosis contain ubiquitin and phosphorylated neurofilaments epitopes. Neuropathology 11:11–20
12.
go back to reference Mulder DW, Kurland LT, Offord KP, Beard CM (1986) Familial adult motor neuron disease: amyotrophic lateral sclerosis. Neurology 36:511–517PubMed Mulder DW, Kurland LT, Offord KP, Beard CM (1986) Familial adult motor neuron disease: amyotrophic lateral sclerosis. Neurology 36:511–517PubMed
13.
go back to reference Murayama S, Ookawa Y, Mori H, Nakano I, Ihara Y, Kuzuhara S, Tomonaga M (1989) Immunocytochemical and ultrastructural study of Lewy body-like hyaline inclusions in familial amyotrophic lateral sclerosis. Acta Neuropathol 78:143–152PubMedCrossRef Murayama S, Ookawa Y, Mori H, Nakano I, Ihara Y, Kuzuhara S, Tomonaga M (1989) Immunocytochemical and ultrastructural study of Lewy body-like hyaline inclusions in familial amyotrophic lateral sclerosis. Acta Neuropathol 78:143–152PubMedCrossRef
14.
go back to reference Nakano R, Sato S, Inuzuka T, Sakimura K, Mishina M, Takahashi H, Ikuta F, Honma Y, Fujii J, Taniguchi N, Tsuji S (1994) A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis. Biochem Biophys Res Commun 200:695–703sPubMedCrossRef Nakano R, Sato S, Inuzuka T, Sakimura K, Mishina M, Takahashi H, Ikuta F, Honma Y, Fujii J, Taniguchi N, Tsuji S (1994) A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis. Biochem Biophys Res Commun 200:695–703sPubMedCrossRef
15.
go back to reference Neumann M, Sampathu DM, Kwong LK, Truax A, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM-Y (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedCrossRef Neumann M, Sampathu DM, Kwong LK, Truax A, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM-Y (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedCrossRef
16.
go back to reference Okamoto K, Hirai S, Amari M, Watanabe M, Sakurai A (1993) Bunina bodies in amyotrophic lateral sclerosis immunostained with rabbit anti-cystatin C serum. Neurosci Lett 162:125–128PubMedCrossRef Okamoto K, Hirai S, Amari M, Watanabe M, Sakurai A (1993) Bunina bodies in amyotrophic lateral sclerosis immunostained with rabbit anti-cystatin C serum. Neurosci Lett 162:125–128PubMedCrossRef
17.
go back to reference Okamoto K, Morimatsu M, Hirai S, Ishida Y (1980) Intracytoplasmic inclusions (Bunina bodies) in amyotrophic lateral sclerosis. Acta Pathol Jpn 30:591–597PubMed Okamoto K, Morimatsu M, Hirai S, Ishida Y (1980) Intracytoplasmic inclusions (Bunina bodies) in amyotrophic lateral sclerosis. Acta Pathol Jpn 30:591–597PubMed
18.
go back to reference Ou SH, Wu F, Harrich D, García-Martínez LF, Gaynor RB (1995) Cloning and characterization of a novel cellular protein, TDP-43, that bind to human immunodeficiency virus type I TAR DNA sequence motifs. J Viol 69:3584–3596 Ou SH, Wu F, Harrich D, García-Martínez LF, Gaynor RB (1995) Cloning and characterization of a novel cellular protein, TDP-43, that bind to human immunodeficiency virus type I TAR DNA sequence motifs. J Viol 69:3584–3596
19.
go back to reference Piao Y-S, Wakabayashi K, Kakita A, Yamada M, Hayashi S, Morita T, Ikuta F, Oyanagi K, Takahashi H (2003) Neuropathology with clinical correlations of sporadic amyotrophic lateral sclerosis: 102 autopsy cases examined between 1962 and 2000. Brain Pathol 13:10–22PubMedCrossRef Piao Y-S, Wakabayashi K, Kakita A, Yamada M, Hayashi S, Morita T, Ikuta F, Oyanagi K, Takahashi H (2003) Neuropathology with clinical correlations of sporadic amyotrophic lateral sclerosis: 102 autopsy cases examined between 1962 and 2000. Brain Pathol 13:10–22PubMedCrossRef
20.
go back to reference Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, Oregan JP, Deng H-X, Rahmani Z, Krizus A, McKenna-Yasck D,Cayabyab A, Gaston SM, Berger R,Tanzi RE, Halperin JJ, Herzfeldt B, Van den Bergh R, Hung W-Y, Bird T, Deng G, Mulder DW, Smyth C, Laing NG, Soriano E, Pericak-Vance MA, Haines J, Rouleau GA, Gusella JS, Horritz HR, Brown RH (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62PubMedCrossRef Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, Oregan JP, Deng H-X, Rahmani Z, Krizus A, McKenna-Yasck D,Cayabyab A, Gaston SM, Berger R,Tanzi RE, Halperin JJ, Herzfeldt B, Van den Bergh R, Hung W-Y, Bird T, Deng G, Mulder DW, Smyth C, Laing NG, Soriano E, Pericak-Vance MA, Haines J, Rouleau GA, Gusella JS, Horritz HR, Brown RH (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62PubMedCrossRef
21.
go back to reference Sasaki S, Murayama S (1992) Ultrastructural study of skein-like inclusions in anterior horn neurons of patients with motor neuron disease. Neurosci Lett 147:121–124PubMedCrossRef Sasaki S, Murayama S (1992) Ultrastructural study of skein-like inclusions in anterior horn neurons of patients with motor neuron disease. Neurosci Lett 147:121–124PubMedCrossRef
22.
go back to reference Shibata N, Hirano A, Kobayashi M, Siddique T, Deng HX, Hung WY, Kato T, Asayama K (1996) Intense superoxide dismutase-1 immunoreactivity in intracytoplasmic hyaline inclusions of familial amyotrophic lateral sclerosis with posterior column involvement. J Neuropathol Exp Neurol 55:481–490PubMed Shibata N, Hirano A, Kobayashi M, Siddique T, Deng HX, Hung WY, Kato T, Asayama K (1996) Intense superoxide dismutase-1 immunoreactivity in intracytoplasmic hyaline inclusions of familial amyotrophic lateral sclerosis with posterior column involvement. J Neuropathol Exp Neurol 55:481–490PubMed
23.
go back to reference Tagawa A, Tan C-F, Kikugawa K, Fukase M, Nakano R, Onodera O, Nishizawa M, Takahashi H (2007) Familial amyotrophic lateral sclerosis: a SOD1-unrelated Japanese family of bulbar type with Bunina bodies and ubiquitin-positive skein-like inclusions in lower motor neurons. Acta Neuropathol 113:205–211PubMedCrossRef Tagawa A, Tan C-F, Kikugawa K, Fukase M, Nakano R, Onodera O, Nishizawa M, Takahashi H (2007) Familial amyotrophic lateral sclerosis: a SOD1-unrelated Japanese family of bulbar type with Bunina bodies and ubiquitin-positive skein-like inclusions in lower motor neurons. Acta Neuropathol 113:205–211PubMedCrossRef
24.
go back to reference Takahashi H (1992) Bunina body in amyotrophic lateral sclerosis (in Japanese). No To Shinkei 44:525–532PubMed Takahashi H (1992) Bunina body in amyotrophic lateral sclerosis (in Japanese). No To Shinkei 44:525–532PubMed
25.
go back to reference Takahashi H, Makifuchi T, Nakano R, Sato S, Inuzuka T, Sakimura K, Mishina M, Honma Y, Tsuji S, Ikuta F (1994) Familial amyotrophic lateral sclerosis with a mutation in the Cu/Zn superoxide dismutase gene. Acta Neuropathol 88:185–188PubMed Takahashi H, Makifuchi T, Nakano R, Sato S, Inuzuka T, Sakimura K, Mishina M, Honma Y, Tsuji S, Ikuta F (1994) Familial amyotrophic lateral sclerosis with a mutation in the Cu/Zn superoxide dismutase gene. Acta Neuropathol 88:185–188PubMed
26.
go back to reference Tan C-F, Piao Y-S, Hayashi S, Obata H, Umeda Y, Sato M, Fukushima T, Nakano R, Tsuji S, Takahashi H (2004) Familial amyotrophic lateral sclerosis with bulbar onset and a novel Asp101Tyr Cu/Zn superoxide dismutase gene mutation. Acta Neuropathol 108:332–336PubMedCrossRef Tan C-F, Piao Y-S, Hayashi S, Obata H, Umeda Y, Sato M, Fukushima T, Nakano R, Tsuji S, Takahashi H (2004) Familial amyotrophic lateral sclerosis with bulbar onset and a novel Asp101Tyr Cu/Zn superoxide dismutase gene mutation. Acta Neuropathol 108:332–336PubMedCrossRef
27.
go back to reference Tomonaga M, Saito M, Yoshimura M, Shimada H, Tohgi H (1978) Ultrastructure of the Bunina bodies in amyotrophic lateral sclerosis. Acta Neuropathol 42:81–86PubMedCrossRef Tomonaga M, Saito M, Yoshimura M, Shimada H, Tohgi H (1978) Ultrastructure of the Bunina bodies in amyotrophic lateral sclerosis. Acta Neuropathol 42:81–86PubMedCrossRef
28.
go back to reference Wakabayashi K, Piao Y-S, Hayashi S, Kakita A, Yamada M, Takahashi H (2001) Ubiquitinated neuronal inclusions in the neostriatum in patients with amyotrophic lateral sclerosis with and without dementia—a study of 60 patients 31 to 87 years of age. Clin Neuropathol 20:47–52PubMed Wakabayashi K, Piao Y-S, Hayashi S, Kakita A, Yamada M, Takahashi H (2001) Ubiquitinated neuronal inclusions in the neostriatum in patients with amyotrophic lateral sclerosis with and without dementia—a study of 60 patients 31 to 87 years of age. Clin Neuropathol 20:47–52PubMed
29.
go back to reference Wang H-Y, Wang I-F, Bose J, Shen C-KJ (2004) Structural diversity and functional implications of the eukaryotic TDP gene family. Genomics 83:130–139PubMedCrossRef Wang H-Y, Wang I-F, Bose J, Shen C-KJ (2004) Structural diversity and functional implications of the eukaryotic TDP gene family. Genomics 83:130–139PubMedCrossRef
Metadata
Title
TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation
Publication date
01-05-2007
Published in
Acta Neuropathologica / Issue 5/2007
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-007-0206-9

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