Up-regulation of pro-nerve growth factor, neurotrophin receptor p75, and sortilin is associated with retrovirus-induced spongiform encephalomyelopathy.
Up-regulation of pro-nerve growth factor, neurotrophin receptor p75, and sortilin is associated with retrovirus-induced spongiform encephalomyelopathy.
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前神经生长因子、神经营养蛋白受体 p75 和分拣蛋白的上调与逆转录病毒诱导的海绵状脑脊髓病有关。
DOI：
10.1016/j.brainres.2008.02.085
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发表时间：
2008
期刊：
影响因子：
2.9
通讯作者：
Wong,PaulKY
中科院分区：
文献类型：
--
作者：
Stoica,George;Lungu,Gina;Kim,Hun-Taek;Wong,PaulKY
由Moloney小鼠白血病病毒(MoMuLV-Ts1)的神经致病温度敏感突变体Ts1引起的进行性海绵状脑脊髓病，导致运动神经元丢失，而不是直接的神经元感染。我们以前曾报道过Ts1介导的小鼠神经元变性具有多因素的发病机制。在此，我们报道了在感染Ts1的中枢神经系统(CNS)中，激活的神经细胞在海绵状改变的区域显示出强烈的神经生长因子(ProNGF)、神经营养素受体p75(P75NTR)和山梨素的免疫反应。由于最近的研究表明proNGF在与辅受体p75NTR/sortilin结合后在诱导神经元死亡方面比成熟NGF更活跃，我们推测proNGF、sortilin和p75NTR的过度表达在Ts1诱导的神经元变性中发挥了作用。我们发现，与未感染的对照组织相比，感染Ts1的脑干组织中proNGF和p75NTR显著增加，而Sortilin、mRNA和蛋白质却没有显著增加。在Ts1感染的脑干中，p75NTR有广泛的酪氨酸磷酸化，p75NTR是其激活的标志，变性神经元中有大量的p75NTR。我们探讨了Ts1病毒感染培养的永生化的C1星形胶质细胞是否也存在体内proNGF表达的增加。只有在加入成纤维细胞生长因子(FGF-1)后，感染的C1细胞的proNGF水平才显著高于对照细胞。我们还发现，在Ts1感染的小鼠中枢神经系统中，成纤维细胞生长因子-1的表达增加。我们的研究结果提示，在Ts1诱导的神经退行性变的发病过程中，成纤维细胞生长因子-1信号通路可能与神经细胞内proNGF的过度表达有关。这项研究为ProNGF及其受体在Ts1诱导的神经变性中的可能作用提供了新的体内见解。
The progressive spongiform encephalomyelopathy caused by ts1, a neuropathogenic temperature-sensitive mutant of Moloney murine leukemia virus (MoMuLV-ts1), results in motor neuronal loss without direct neuronal infection. We have previously reported that ts1-mediated neuronal degeneration in mice has a multifactorial pathogenesis. Here, we report that in the ts1-infected central nervous system (CNS) activated neural cells showed intense immunoreactivity for pro-nerve growth factor (proNGF), neurotrophin receptor p75 (p75NTR), and sortilin in the areas showing spongiform changes. Since recent studies suggested that proNGF is more active than mature NGF in inducing neuronal death after binding to co-receptors p75NTR/sortilin, we hypothesized that overexpression of proNGF, sortilin and p75NTRplay a role in ts1-induced neurodegeneration. We found that proNGF and p75NTR, but not sortilin, mRNA and protein were significantly elevated in ts1-infected brainstem compared to non-infected control tissue. There was extensive tyrosine phosphorylation of p75NTR, a marker for its activation, in ts1-infected brainstem with abundance in degenerating neurons. We explored whether the increase in the in vivo proNGF expression also occurs in cultured immortalized C1 astrocytes infected by ts1 virus. The proNGF level was significantly increased in infected C1 cells compared to control cells only after addition of fibroblast growth factor (FGF-1). We also showed increased expression of FGF-1 in the CNS of ts1-infected mice. Our findings suggest that the FGF-1 signaling pathway may be responsible for the overexpression of proNGF in neural cells during pathogenesis of ts1-induced neurodegeneration. This study provides new in vivo insights into the possible role of proNGF and its receptors in ts1-induced neurodegeneration.