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Altered distributions of nucleocytoplasmic transport-related proteins in the spinal cord of a mouse model of amyotrophic lateral sclerosis

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Abstract

Recent investigations have indicated that the nucleocytoplasmic transport system is essential for maintaining cell viability and cellular functions and that its dysfunction could lead to certain disorders. To investigate the involvement of this system in the pathomechanisms of amyotrophic lateral sclerosis (ALS), we examined the immunohistochemical localization of proteins associated with nucleocytoplasmic transport in the lumbar spinal cord in a mutant SOD1 (G93A) transgenic mouse model of ALS. This model is widely used for ALS research, and the mutant mice are known to exhibit neuronal loss and Lewy body-like hyaline inclusions (LBHIs) in the anterior horns, similar to the pathology seen in familial ALS patients associated with an SOD1 mutation and in several other transgenic rodent models. Using antibodies against the importin beta family of proteins, the major carrier proteins of nucleocytoplasmic transport, and those against their adapter protein, importin alpha, we found that the immunoreactivities were decreased within the nuclei and increased within the cytoplasm of a subset of the surviving anterior horn cells of the transgenic mice. In addition, LBHIs were invariably reactive toward these antibodies. Furthermore, the immunoreactivities for histone H1 and beta-catenin, representative cargo proteins transported by importin beta-dependent and beta-independent nucleocytoplasmic transport pathways, respectively, showed distributions similar to those for importin beta family and importin alpha proteins. The altered distributions of these proteins were not associated with caspase-3 expression, suggesting that the findings are unlikely to be a manifestation of apoptotic processes. Chronological quantitative analysis of importin beta-immunostained sections from the transgenic mice revealed a statistically significant progressive decrease in the proportion of the anterior horn cells exhibiting a more intense reactivity for these proteins in the nucleus than in the cytoplasm. To the contrary, we found that the anterior horn cells with the immunoreactivity in their cytoplasm, being more pronounced than that in their nucleus, were significantly increased in number along with the disease progression. This is the first report investigating nucleocytoplasmic transport in the ALS model mouse, and our present results imply that its dysfunction could be involved in the pathomechanisms underlying ALS.

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Acknowledgments

We express our sincere appreciation to Professor Asao Hirano (Division of Neuropathology, Department of Pathology, Montefiore Medical Center) for helpful comments, and to Miss Tomoko Takemi for her technical assistance. This work was supported in part by a grant-in-aid for scientific research from the Japan Society for the Promotion of Science (No. 15590917) and by a grant from Kansai Medical University (Research Grant B, 2005).

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Authors and Affiliations

  1. Department of Neurology, Kansai Medical University, 10-15, Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan

    Jianhua Zhang, Hidefumi Ito, Reika Wate, Shizuo Ohnishi, Satoshi Nakano & Hirofumi Kusaka

  2. Department of Neurology, Harbin Medical University, No.23 Youzheng Street, Nangang District, Harbin, Heilongjiang, 150001, China

    Jianhua Zhang

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  1. Jianhua Zhang
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Correspondence to Hidefumi Ito.

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Zhang, J., Ito, H., Wate, R. et al. Altered distributions of nucleocytoplasmic transport-related proteins in the spinal cord of a mouse model of amyotrophic lateral sclerosis. Acta Neuropathol 112, 673–680 (2006). https://doi.org/10.1007/s00401-006-0130-4

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