TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation
- 1k Downloads
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.
Keywords43-kDa TAR DNA-binding protein (TDP-43) Amyotrophic lateral sclerosis Cu/Zn superoxide dismutase (SOD1) Ubiquitin-positive inclusion Bunina body
We thank C. Tanda, J. Takasaki, N. Kaneko, Y. Ota and S. Egawa for their technical assistance. This work was supported by a grant from the Research Committee on Neurodegenerative Diseases, Ministry of Health, Labor and Welfare, Japan.
- 1.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 351:602–611PubMedCrossRefGoogle Scholar
- 2.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.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 261:1047–1051PubMedCrossRefGoogle Scholar
- 11.Mizusawa H, Hirano A, Yen S-H (1991) Anterior horn cell inclusions in familial amyotrophic lateral sclerosis contain ubiquitin and phosphorylated neurofilaments epitopes. Neuropathology 11:11–20Google Scholar
- 15.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 314:130–133PubMedCrossRefGoogle Scholar
- 18.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 69:3584–3596Google Scholar
- 20.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 362:59–62PubMedCrossRefGoogle Scholar
- 22.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 55:481–490PubMedGoogle Scholar
- 23.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 113:205–211PubMedCrossRefGoogle Scholar