Acta Neuropathologica

, Volume 118, Issue 4, pp 553–560

Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado–Joseph disease

  • Chun-Feng Tan
  • Mitsunori Yamada
  • Yasuko Toyoshima
  • Akio Yokoseki
  • Yukari Miki
  • Yasuhiro Hoshi
  • Hiroyuki Kaneko
  • Takeshi Ikeuchi
  • Osamu Onodera
  • Akiyoshi Kakita
  • Hitoshi Takahashi
Original Paper

DOI: 10.1007/s00401-009-0552-x

Cite this article as:
Tan, CF., Yamada, M., Toyoshima, Y. et al. Acta Neuropathol (2009) 118: 553. doi:10.1007/s00401-009-0552-x

Abstract

Pathological transactivation-responsive DNA-binding protein 43 (TDP-43) has been identified as a component of ubiquitinated inclusions in frontotemporal lobar degeneration with motor neuron disease, as well as in sporadic and some forms of familial amyotrophic lateral sclerosis. To clarify whether pathological TDP-43 is present in other neurodegenerative diseases involving the motor neuron system, we immunohistochemically examined the brain and spinal cord affected by two CAG repeat (polyglutamine) diseases, Machado–Joseph disease (MJD) and spinal and bulbar muscular atrophy (SBMA), using polyclonal antibody against TDP-43. In all the MJD cases, TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs), although few in number, were found only in the lower motor neurons in the brainstem and spinal cord. TDP-43-ir NCIs appeared as linear wisp-like, skein-like, or thick, somewhat rod-like bodies. These inclusions were also visualized with antibodies against phosphoserines 409 and 410 of TDP-43, and ubiquitin, but were not recognized by antibody against expanded polyglutamine stretches or ataxin-3. The ultrastructure of the TDP-43-ir NCIs was similar to that of the inclusions seen in sporadic ALS, consisting of bundles of parallel filaments. None of the SBMA cases showed abnormal TDP-43 immunoreactivity in any of the regions examined. Immunoblot analysis failed to recognize hyperphosphorylated TDP-43 at ~23 kDa in two MJD cases examined. However, the immunohistochemical findings strongly suggested that in MJD, in addition to the polyglutamine-dependent disease process, TDP-43-related pathogenesis is associated with degeneration and death of the lower motor neurons.

Keywords

Machado–Joseph diseaseTDP-43Lower motor neuronNeuronal cytoplasmic inclusionAmyotrophic lateral sclerosis

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Chun-Feng Tan
    • 1
  • Mitsunori Yamada
    • 1
    • 2
  • Yasuko Toyoshima
    • 1
  • Akio Yokoseki
    • 3
  • Yukari Miki
    • 1
  • Yasuhiro Hoshi
    • 1
  • Hiroyuki Kaneko
    • 3
  • Takeshi Ikeuchi
    • 4
  • Osamu Onodera
    • 4
  • Akiyoshi Kakita
    • 5
  • Hitoshi Takahashi
    • 1
  1. 1.Department of Pathology, Brain Research InstituteUniversity of NiigataNiigataJapan
  2. 2.Department of Clinical Research, National Hospital OrganizationSaigata National HospitalOhgata-ku, JohetsuJapan
  3. 3.Department of Neurology, Brain Research InstituteUniversity of NiigataNiigataJapan
  4. 4.Department of Molecular Neuroscience, Resource Branch for Brain Disease Research, Brain Research InstituteUniversity of NiigataNiigataJapan
  5. 5.Department of Pathological Neuroscience, Resource Branch for Brain Disease Research, Brain Research InstituteUniversity of NiigataNiigataJapan