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
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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DOI：
10.1007/s00401-003-0708-z
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发表时间：
2003-08-01
影响因子：
12.7
通讯作者：
Ohama, E
中科院分区：
文献类型：
--
作者：
Kato, S;Funakoshi, H;Ohama, E
为了阐明散发性肌萎缩性侧索硬化症（SALS）和家族性肌萎缩性侧索硬化症（FALS）伴有超氧化物歧化酶1 （SOD1）突变的残余前角细胞的营养机制，我们研究了肝细胞生长因子（HGF）（一种新型神经营养因子）及其受体c-Met的免疫组织化学表达。在正常受试者中，几乎所有前角细胞都对抗hgf和抗c- met抗体具有免疫反应性，而星形胶质细胞和少突胶质细胞没有明显的免疫反应性。组织学上，ALS患者的脊髓前角细胞数量随着疾病进展而减少。免疫组织化学分析显示，随着ALS疾病进展，HGF和c-Met呈阴性的神经元数量增加。然而，在整个病程中，与正常受试者相比，某些残留的前角细胞同时表达HGF和c-Met的强度相同，甚至更强，而不考虑免疫阳性细胞数量的减少。Western blot分析显示，在临床病程为2.5年的SALS患者脊髓中，c-Met被诱导，而在临床病程为11年5个月的SALS患者中，c-Met水平下降。这些结果表明，HGF-c-Met系统的自分泌和/或旁分泌营养支持有助于减弱ALS中残留前角细胞的退化，而在疾病晚期破坏神经元HGF-c-Met系统会加速细胞退化和/或细胞死亡过程。在sod1突变的FALS患者中，一些残留前角细胞中的Lewy体样透明夹杂物（LBHIs）表现出HGF和c-Met的共同聚集，尽管lbhi -携带神经元中HGF和c-Met的细胞质染色强度较弱或为阴性。LBHIs中HGF和c-Met的这种隔离可能提示HGF-c-Met系统的部分破坏，从而加速FALS患者的神经元变性。
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.