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Phosphorylated Smad2/3 immunoreactivity in sporadic and familial amyotrophic lateral sclerosis and its mouse model

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Abstract

Phosphorylated Smad2/3 (pSmad2/3), the central mediators of transforming growth factor (TGF)-beta signaling, were recently identified in tau-positive inclusions in certain neurodegenerative disorders. To clarify whether the localization of pSmad2/3 is altered in amyotrophic lateral sclerosis (ALS), we immunohistochemically examined spinal cords from sporadic ALS (SALS), from familial ALS (FALS) patients with the A4V mutation in their Cu/Zn superoxide dismutase (SOD1) gene, and from G93A mutant SOD1 transgenic (mSOD1 Tg) mice. In control spinal cords, pSmad2/3 immunoreactivity was observed exclusively in neuronal and glial nuclei. In SALS and FALS patients the nuclei showed increased immunoreactivity for pSmad2/3. Noticeably, round hyaline inclusions (RHIs) and skein-like inclusions of SALS patients were immunoreactive for pSmad2/3. Double immunofluorescence staining for pSmad2/3 and transactive response-DNA-binding protein (TDP)-43 revealed co-localization of these proteins within RHIs. In contrast, Bunina bodies in SALS and Lewy body-like hyaline inclusions (LBHIs) in FALS were devoid of labeling for pSmad2/3. Similarly, in the mSOD1 Tg mice pSmad2/3 immunoreactivity was increased in the nuclei, while LBHIs were not labeled. These findings suggest increased TGF-beta-Smad signaling in SALS, FALS, and mSOD1 Tg mice, as well as impaired TGF-beta signal transduction in RHI-bearing neurons of SALS patients, presumably at the step of pSmad2/3 translocation into the nucleus. The pathomechanisms, including the process of inclusion development, appears to be different between SALS and mSOD1-related FALS or Tg mice.

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Acknowledgments

We express our sincere appreciation to Drs. Kengo Fujita, Yoshimi Kinoshita, and Makoto Nishii, as well as to Miss Tomoko Takemi, for their assistance.

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Authors and Affiliations

  1. Department of Neurology, Kansai Medical University, 10-15, Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan

    Masataka Nakamura, Hidefumi Ito, Reika Wate, Satoshi Nakano & Hirofumi Kusaka

  2. Division of Neuropathology, Department of Pathology, Montefiore Medical Center, New York, NY, 10467-2490, USA

    Asao Hirano

Authors
  1. Masataka Nakamura
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  2. Hidefumi Ito
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  3. Reika Wate
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  4. Satoshi Nakano
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  6. Hirofumi Kusaka
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Correspondence to Hidefumi Ito.

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Nakamura, M., Ito, H., Wate, R. et al. Phosphorylated Smad2/3 immunoreactivity in sporadic and familial amyotrophic lateral sclerosis and its mouse model. Acta Neuropathol 115, 327–334 (2008). https://doi.org/10.1007/s00401-007-0337-z

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  • DOI: https://doi.org/10.1007/s00401-007-0337-z

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