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

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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.

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Acknowledgments

We thank C. Tanda, J. Takasaki, H. Saito and S. Egawa for their technical assistance, and M. Machida for help in preparing the manuscript. This work was supported by Grants-in-Aid for Scientific Research (17300109, 20240037) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, and a grant from the Research Committee for Ataxic Diseases, the Ministry of Health, Labour and Welfare, Japan.

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Author notes

  1. Mitsunori Yamada

    Present address: Department of Clinical Research, National Hospital Organization, Saigata National Hospital, 468-1 Saigata, Ohgata-ku, Johetsu, Niigata, 949-3193, Japan

Authors and Affiliations

  1. Department of Pathology, Brain Research Institute, University of Niigata, 1-757 Asahimachi, Niigata, 951-8585, Japan

    Chun-Feng Tan, Mitsunori Yamada, Yasuko Toyoshima, Yukari Miki, Yasuhiro Hoshi & Hitoshi Takahashi

  2. Department of Neurology, Brain Research Institute, University of Niigata, Niigata, 951-8585, Japan

    Akio Yokoseki & Hiroyuki Kaneko

  3. Department of Molecular Neuroscience, Resource Branch for Brain Disease Research, Brain Research Institute, University of Niigata, Niigata, 951-8585, Japan

    Takeshi Ikeuchi & Osamu Onodera

  4. Department of Pathological Neuroscience, Resource Branch for Brain Disease Research, Brain Research Institute, University of Niigata, Niigata, 951-8585, Japan

    Akiyoshi Kakita

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  1. Chun-Feng Tan
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Correspondence to Yasuko Toyoshima.

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Tan, CF., Yamada, M., Toyoshima, Y. et al. Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado–Joseph disease. Acta Neuropathol 118, 553–560 (2009). https://doi.org/10.1007/s00401-009-0552-x

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  • DOI: https://doi.org/10.1007/s00401-009-0552-x

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