Rinsho Shinkeigaku (Clinical Neurology)

The 51st Annual Meeting of the Japanese Society of Neurology

The clinical and pathological spectrum of TDP-43 associated ALS

Osamu Onodera, M.D.1), Akio Yokoseki, M.D.2), Chun-Feng Tan, M.D.3), Tomohiko Ishihara, M.D.1)2), Yasushi Nishiira, M.D.3), Yasuko Toyoshima, M.D.3), Akiyoshi Kakita, M.D.3), Masatoyo Nishizawa, M.D.2) and Hitoshi Takahashi, M.D.3)

1)Department of Molecular Neuroscience, Center for Bioresource-based Researches, Brain Research Institute, Niigata University
2)Department of Neurology, Brain Research Institute, Niigata University
3)Department of Pathology, Center for Bioresource-based Researches, Brain Research Institute, Niigata University

The molecular pathogenesis of amyotrophic lateral sclerosis (ALS) is unclear. TAR DNA-binding proteins of 43 KDa (TDP-43) immunopositive cytoplasmic inclusions have been found in glia and neurons of ALS patients. The discovery of TDP-43 mutations in ALS patients indicates a direct role of TDP-43 in ALS. More than 30 mutations in the TDP-43 gene have been identified in patients with familial and sporadic ALS. ALS with a TDP-43 mutation is classified as ALS-10. The clinical features of ALS-10 are quite similar to those of sporadic ALS. Furthermore, the neuropathological findings for ALS-10, including TDP-43 immunopositive inclusions and Bunina bodies, are identical to those in sporadic ALS. Most of the mutations are located in the C-terminus of TDP-43, which may function as a binding domain of heterogeneous nuclear ribonucleoprotein. Frontotemporal lobar degeneration: FTLD and FTLD MND (motor neuron disease) also have TDP-43 immunopositive inclusions. These disorders have been named as TDP-43 proteinopathy. However, patients with TDP-43 mutations rarely develop FTLD. Causative genes for familial FTLD and FTLD/MND are not linked to the TDP-43 gene. Thus, other factors may contribute to the TDP-43 pathology in these diseases. Further analysis is required to elucidate the molecular mechanism of ALS-10 and TDP-43 proteinopathy.
Full Text of this Article in Japanese PDF (180K)

(CLINICA NEUROL, 50: 940|942, 2010)
key words: TDP-43, ALS-10, pathology, SALS, FTLD/MND

(Received: 22-May-10)