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Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia

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Abstract

To elucidate the maturation process of TDP-43-positive neuronal inclusions, we immunohistochemically and immunoelectron-microscopically examined multiple areas from the brain and spinal cord from ten patients with amyotrophic lateral sclerosis (ALS) and 25 control subjects. TDP-43 immunohistochemistry demonstrated three types of inclusions in ALS: skein-like, round, and dot-like inclusions. Skein-like inclusions were found in all cases of ALS. Dot-like inclusions were found in the anterior horn in seven cases of ALS, all of whom had round inclusions, but not in cases without round inclusions. In addition, careful examination revealed two types of diffuse punctate cytoplasmic staining: linear wisps and punctate granules. Linear wisps were present in all cases of ALS but in none of 25 controls. In contrast, punctate granules were detected in all cases of ALS as well as in five of 13 normal and in seven of 12 diseased controls. Immunoelectron-microscopy revealed that skein-like inclusions consisted of granule-associated parallel filaments. Round and dot-like inclusions were composed of granulo-filamentous structures. However, punctate granules corresponded to the mitochondria and were not immunostained with anti-ubiquitin, indicating that punctate granules represent cross-reaction. We assumed that linear wisps (“fine skein”) aggregate as thicker and longer threads (“coarse skein”), whereas round inclusions arise from dot-like inclusions. These findings suggest that there are differences in the formation process between skein-like and round inclusions, despite the antigenic and ultrastructural similarities.

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Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (to K.W.) and a grant from the Research Committee on Neurodegenerative Diseases, Ministry of Health, Labor and Welfare, Japan (to H.T.). The authors wish to express their gratitude to M. Nakata for her technical assistance.

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Authors and Affiliations

  1. Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan

    Fumiaki Mori, Kunikazu Tanji, Hai-Xin Zhang & Koichi Wakabayashi

  2. Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan

    Yasushi Nishihira, Chun-Feng Tan & Hitoshi Takahashi

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  1. Fumiaki Mori
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  2. Kunikazu Tanji
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  3. Hai-Xin Zhang
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  4. Yasushi Nishihira
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  5. Chun-Feng Tan
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  6. Hitoshi Takahashi
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  7. Koichi Wakabayashi
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Correspondence to Fumiaki Mori.

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Mori, F., Tanji, K., Zhang, HX. et al. Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia. Acta Neuropathol 116, 193–203 (2008). https://doi.org/10.1007/s00401-008-0396-9

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