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

• Published in: Acta neuropathologica 2008-03, Vol.115 (3), p.327-334
• Main Authors: Nakamura, Masataka, Ito, Hidefumi, Wate, Reika, Nakano, Satoshi, Hirano, Asao, Kusaka, Hirofumi
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Alzheimer's disease; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Cell Nucleus - metabolism; Disease Models, Animal; Female; Fluorescent Antibody Technique; Growth factors; Humans; Immunohistochemistry; Inclusion Bodies - metabolism; Inclusion Bodies - pathology; Kinases; Localization; Male; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Middle Aged; Mutation; Neurons; Neurosciences; Original Paper; Pathogenesis; Pathology; Phosphorylation; Protein Transport - physiology; Proteins; Signal transduction; Smad2 Protein - metabolism; Smad3 Protein - biosynthesis; Spinal Cord - metabolism; Spinal Cord - pathology
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-007-0337-z

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.