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Expression of hepatocyte growth factor and c-Met in the anterior horn cells of the spinal cord in the patients with amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS and familial ALS with superoxide dismutase 1 gene mutation

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Abstract

To clarify the trophic mechanism of residual anterior horn cells affected by sporadic amyotrophic lateral sclerosis (SALS) and familial ALS (FALS) with superoxide dismutase 1 (SOD1) mutations, we investigated the immunohistochemical expression of hepatocyte growth factor (HGF), a novel neurotrophic factor, and its receptor, c-Met. In normal subjects, immunoreactivity to both anti-HGF and anti-c-Met antibodies was observed in almost all anterior horn cells, whereas no significant immunoreactivity was observed in astrocytes and oligodendrocytes. Histologically, the number of spinal anterior horn cells in ALS patients decreased along with disease progression. Immunohistochemically, the number of neurons negative for HGF and c-Met increased with ALS disease progression. However, throughout the course of the disease, certain residual anterior horn cells co-expressed both HGF and c-Met with the same, or even stronger intensity in comparison with those of normal subjects, irrespective of the reduction in the number of immunopositive cells. Western blot analysis revealed that c-Met was induced in the spinal cord of a patient with SALS after a clinical course of 2.5 years, whereas the level decreased in a SALS patient after a clinical course of 11 years 5 months. These results suggest that the autocrine and/or paracrine trophic support of the HGF-c-Met system contributes to the attenuation of the degeneration of residual anterior horn cells in ALS, while disruption of the neuronal HGF-c-Met system at an advanced disease stage accelerates cellular degeneration and/or the process of cell death. In SOD1-mutated FALS patients, Lewy body-like hyaline inclusions (LBHIs) in some residual anterior horn cells exhibited co-aggregation of both HGF and c-Met, although the cytoplasmic staining intensity for HGF and c-Met in the LBHI-bearing neurons was either weak or negative. Such sequestration of HGF and c-Met in LBHIs may suggest partial disruption of the HGF-c-Met system, thereby contributing to the acceleration of neuronal degeneration in FALS patients.

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Acknowledgements

This study was supported in part by a Grant-in-Aid for Scientific Research (c) (2) from the Ministry of Education, Culture, Sports, Science and Technology for Japan (S.K.: 13680821) and by a Grant from the Ministry of Health, Labor and Welfare (S.K. and H.F.).

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Authors and Affiliations

  1. Department of Neuropathology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Nishi-cho 36-1, 683-8504, Yonago, Japan

    Shinsuke Kato & Eisaku Ohama

  2. Division of Molecular Regenerative Medicine, Course of Advanced Medicine, Osaka University Graduate School of Medicine, 565-0871, Osaka, Japan

    Hiroshi Funakoshi & Toshikazu Nakamura

  3. Division of Pathology, Tottori University Hospital, Yonago, Japan

    Masako Kato

  4. Department of Neurology, Jichi Medical College, Tochigi, Japan

    Imaharu Nakano

  5. Division of Neuropathology, Department of Pathology, Montefiore Medical Center, Bronx, New York, USA

    Asao Hirano

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  1. Shinsuke Kato
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  2. Hiroshi Funakoshi
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  3. Toshikazu Nakamura
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  4. Masako Kato
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Correspondence to Shinsuke Kato.

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Kato, S., Funakoshi, H., Nakamura, T. et al. Expression of hepatocyte growth factor and c-Met in the anterior horn cells of the spinal cord in the patients with amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS and familial ALS with superoxide dismutase 1 gene mutation. Acta Neuropathol 106, 112–120 (2003). https://doi.org/10.1007/s00401-003-0708-z

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