Structural insights into human angiogenin variants implicated in Parkinson's disease and Amyotrophic Lateral Sclerosis.
Structural insights into human angiogenin variants implicated in Parkinson's disease and Amyotrophic Lateral Sclerosis.
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DOI：
10.1038/srep41996
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发表时间：
2017-02-08
影响因子：
4.6
通讯作者：
Acharya KR
中科院分区：
文献类型：
--
作者：
Bradshaw WJ;Rehman S;Pham TT;Thiyagarajan N;Lee RL;Subramanian V;Acharya KR
已知核糖核酸酶A超家族（也称为RNA酶5）的成员血管生成素（ANG）的突变与肌萎缩侧索硬化症（ALS，运动神经元疾病）（散发性和家族性）和帕金森病（PD）相关。在我们以前的研究中，我们已经表明ANG在神经外胚层分化的神经元中表达，并且它具有神经营养和神经保护功能。此外，在对选择性ANG-ALS变体的广泛研究中，我们将结构变化与对神经元存活的影响和在神经元细胞系中诱导应激颗粒的能力相关联。此外，我们已经确定ANG-ALS变体影响催化位点的结构，并且降低或增加RNA酶活性影响神经元存活。表达ANG-ALS变体的神经元细胞系也缺乏形成应激颗粒的能力。在这里，我们报告了11个新的ANG-PD/ALS变体的详细实验结构研究，这将有助于理解其在PD和ALS中作用的分子基础。
Mutations in Angiogenin (ANG), a member of the Ribonuclease A superfamily (also known as RNase 5) are known to be associated with Amyotrophic Lateral Sclerosis (ALS, motor neurone disease) (sporadic and familial) and Parkinson’s Disease (PD). In our previous studies we have shown that ANG is expressed in neurons during neuro-ectodermal differentiation, and that it has both neurotrophic and neuroprotective functions. In addition, in an extensive study on selective ANG-ALS variants we correlated the structural changes to the effects on neuronal survival and the ability to induce stress granules in neuronal cell lines. Furthermore, we have established that ANG-ALS variants which affect the structure of the catalytic site and either decrease or increase the RNase activity affect neuronal survival. Neuronal cell lines expressing the ANG-ALS variants also lack the ability to form stress granules. Here, we report a detailed experimental structural study on eleven new ANG-PD/ALS variants which will have implications in understanding the molecular basis underlying their role in PD and ALS.