Characterization of human angiogenin variants implicated in amyotrophic lateral sclerosis
Characterization of human angiogenin variants implicated in amyotrophic lateral sclerosis
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DOI：
10.1021/bi701333h
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发表时间：
2007-10-23
期刊：
影响因子：
2.9
通讯作者：
Acharya, K. Ravi
中科院分区：
文献类型：
--
作者：
Crabtree, Benedict;Thiyagarajan, Nethaji;Acharya, K. Ravi
人血管生成素（ANG）是血管生成素家族（来自胰腺核糖核酸酶A超家族）中第一个被发现的成员，是一种诱导新生血管的血管生成因子。由于它参与肿瘤的生长，并在胰腺和其他几种癌症中表达水平升高，因此受到了广泛关注。最近，ANG的生物学作用已被证明延伸到神经系统。ANG突变与家族性和散发性肌萎缩性侧索硬化症（ALS）有关，ALS是一种致命的神经退行性疾病，其特征是选择性破坏运动神经元。此外，小鼠血管生成素-1已被证明在发育中的神经系统和多能干细胞的神经元分化过程中表达。我们现在已经根据已知的ANG的生化特性对ALS患者中报道的7种ANG变体进行了表征，并进一步研究了其中3种变体的生物学特性。我们的研究结果表明，7种ANG-ALS相关变体中有6种的核糖核溶解活性显著降低或丧失，一些变体也表现出热稳定性的改变。我们报告了我们选择进一步研究的三种变体的细胞增殖和血管生成活性的显着降低。我们对这些ANG变异的生化和结构特征的研究现在为进一步研究确定它们在ALS中的作用奠定了基础。
Human angiogenin (ANG), the first member of the angiogenin family (from the pancreatic ribonuclease A superfamily) to be identified, is an angiogenic factor that induces neovascularization. It has received much attention due to its involvement in the growth of tumors and its elevated expression level in pancreatic and several other cancers. Recently the biological role of ANG has been shown to extend to the nervous system. Mutations in ANG have been linked with familial as well as sporadic forms of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by selective destruction of motor neurons. Furthermore, mouse angiogenin-1 has been shown to be expressed in the developing nervous system and during the neuronal differentiation of pluripotent stem cells. We have now characterized the seven variants of ANG reported in ALS patients with respect to the known biochemical properties of ANG and further studied the biological properties of three of these variants. Our results show that the ribonucleolytic activity of six of the seven ANG-ALS implicated variants is significantly reduced or lost and some variants also show altered thermal stability. We report a significant reduction in the cell proliferative and angiogenic activities of the three variants that we chose to investigate further. Our studies on the biochemical and structural features of these ANG variants now form the basis for further investigations to determine their role(s) in ALS.