Original Paper

Acta Neuropathologica

, Volume 113, Issue 5, pp 535-542

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

  • Chun-Feng TanAffiliated withDepartment of Pathology, Brain Research Institute, University of Niigata Email author 
  • , Hiroto EguchiAffiliated withFirst Department of Internal Medicine (Neurology), Nagasaki University Medical and Dental Hospital
  • , Asako TagawaAffiliated withDepartment of Neurology, Brain Research Institute, University of Niigata
  • , Osamu OnoderaAffiliated withDepartment of Molecular Neuroscience, Resource Branch for Brain Disease Research, Brain Research Institute, University of Niigata
  • , Takuya IwasakiAffiliated withDepartment of Microbiology, Tokyo Metropolitan Institute for Neuroscience
  • , Akira TsujinoAffiliated withFirst Department of Internal Medicine (Neurology), Nagasaki University Medical and Dental Hospital
  • , Masatoyo NishizawaAffiliated withDepartment of Neurology, Brain Research Institute, University of Niigata
  • , Akiyoshi KakitaAffiliated withDepartment of Pathological Neuroscience, Resource Branch for Brain Disease Research CBBR, Brain Research Institute, University of Niigata
  • , Hitoshi TakahashiAffiliated withDepartment of Pathology, Brain Research Institute, University of Niigata

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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.

Keywords

43-kDa TAR DNA-binding protein (TDP-43) Amyotrophic lateral sclerosis Cu/Zn superoxide dismutase (SOD1) Ubiquitin-positive inclusion Bunina body