Influences of dopaminergic lesion on epidermal growth factor-ErbB signals in Parkinson's disease and its model: neurotrophic implication in nigrostriatal neurons
Influences of dopaminergic lesion on epidermal growth factor-ErbB signals in Parkinson's disease and its model: neurotrophic implication in nigrostriatal neurons
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DOI：
10.1111/j.1471-4159.2005.03073.x
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发表时间：
2005-05-01
影响因子：
4.7
通讯作者：
Nawa, H
中科院分区：
文献类型：
--
作者：
Iwakura, Y;Piao, YS;Nawa, H
表皮生长因子（EGF）是一个结构相关的家族成员，包含肝素结合EGF样生长因子（HB-EGF）和转化生长因子α（TGF α），对中脑多巴胺能神经元发挥神经营养活性。为了检查帕金森病（PD）的神经营养异常，我们测量了帕金森病患者和年龄匹配的对照组的死后大脑中EGF，TGF α和HB-EGF的蛋白质含量。EGF和酪氨酸羟化酶的蛋白质水平下降，在前额皮质和纹状体的患者。相比之下，HB-EGF和TGF α水平在两个区域都没有显著改变。EGF受体（ErbB1和ErbB2，而不是ErbB3或ErbB4）在同一前脑区域的表达显著下调。同样的现象在大鼠中被黑质6-羟基多巴胺灌注诱导的多巴胺能损伤所模仿。与对照半球相比，PD模型纹状体中的EGF和ErbB1水平在损伤侧显著降低。通过酪氨酸羟化酶免疫反应性测量，PD模型的纹状体中亚慢性补充EGF局部预防了多巴胺能神经变性。这些研究结果表明，EGF的神经营养活性是由中脑多巴胺能神经元的传入信号维持的，并且在帕金森病患者中受损。
Epidermal growth factor (EGF) is a member of a structurally related family containing heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor alpha (TGF alpha) that exerts neurotrophic activity on midbrain dopaminergic neurons. To examine neurotrophic abnormality in Parkinson's disease (PD), we measured the protein content of EGF, TGF alpha, and HB-EGF in post-mortem brains of patients with Parkinson's disease and age-matched control subjects. Protein levels of EGF and tyrosine hydroxylase were decreased in the prefrontal cortex and the striatum of patients. In contrast, HB-EGF and TGF alpha levels were not significantly altered in either region. The expression of EGF receptors (ErbB1 and ErbB2, but not ErbB3 or ErbB4) was down-regulated significantly in the same forebrain regions. The same phenomenon was mimicked in rats by dopaminergic lesions induced by nigral 6-hydroxydopamine infusion. EGF and ErbB1 levels in the striatum of the PD model were markedly reduced on the lesioned side, compared with the control hemisphere. Subchronic supplement of EGF in the striatum of the PD model locally prevented the dopaminergic neurodegeration as measured by tyrosine hydroxylase immunoreactivity. These findings suggest that the neurotrophic activity of EGF is maintained by afferent signals of midbrain dopaminergic neurons and is impaired in patients with Parkinson's disease.