TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation |
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Authors: | Chun-Feng Tan Hiroto Eguchi Asako Tagawa Osamu Onodera Takuya Iwasaki Akira Tsujino Masatoyo Nishizawa Akiyoshi Kakita Hitoshi Takahashi |
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Institution: | (1) Department of Pathology, Brain Research Institute, University of Niigata, 1-757 Asahimachi, Niigata 951-8585, Japan;(2) First Department of Internal Medicine (Neurology), Nagasaki University Medical and Dental Hospital, Nagasaki 852-8501, Japan;(3) Department of Neurology, Brain Research Institute, University of Niigata, Niigata 951-8585, Japan;(4) Department of Molecular Neuroscience, Resource Branch for Brain Disease Research, Brain Research Institute, University of Niigata, Niigata 951-8585, Japan;(5) Department of Microbiology, Tokyo Metropolitan Institute for Neuroscience, Fuchu 185-8526, Japan;(6) Department of Pathological Neuroscience, Resource Branch for Brain Disease Research CBBR, Brain Research Institute, University of Niigata, Niigata 951-8585, Japan |
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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. |
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Keywords: | 43-kDa TAR DNA-binding protein (TDP-43) Amyotrophic lateral sclerosis Cu/Zn superoxide dismutase (SOD1) Ubiquitin-positive inclusion Bunina body |
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