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Abstract：
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that affects the motoneurons. More than 40 genes are related with ALS, and amyloidogenic proteins like SOD1 and/or TDP-43 mutants are directly involved in the onset of ALS through the formation of polymorphic fibrillogenic aggregates. However, efficacious therapeutic approaches are still lacking. Notably, heterozygous missense mutations affecting the gene coding for RNase 5, an enzyme also called angiogenin (ANG), were found to favor ALS onset. This is also true for the less-studied but angiogenic RNase 4. This review reports the substrate targets and illustrates the neuroprotective role of native ANG in the neo-vascularization of motoneurons. Then, it discusses the molecular determinants of many pathogenic ANG mutants, which almost always cause loss of function related to ALS, resulting in failures in angiogenesis and motoneuron protection. In addition, ANG mutations are sometimes combined with variants of other factors, thereby potentiating ALS effects. However, the activity of the native ANG enzyme should be finely balanced, and not excessive, to avoid possible harmful effects. Considering the interplay of these angiogenic RNases in many cellular processes, this review aims to stimulate further investigations to better elucidate the consequences of mutations in ANG and/or RNase 4 genes, in order to achieve early diagnosis and, possibly, successful therapies against ALS.
摘要：
肌萎缩性侧索硬化症(ALS)是一种影响运动神经元的致命性神经退行性疾病。超过40个基因与ALS有关,和淀粉样蛋白如SOD1和/或TDP-43突变体通过多态性原纤维聚集体的形成直接参与ALS的发作。然而,仍然缺乏有效的治疗方法。值得注意的是,杂合错义突变影响编码RNase5的基因，RNase5是一种也称为血管生成素（ANG）的酶，被发现有利于ALS发作。对于研究较少但血管生成RNase4也是如此。这篇评论报告了底物靶标，并说明了天然ANG在运动神经元新血管形成中的神经保护作用。然后，它讨论了许多致病性ANG突变体的分子决定因素，几乎总是导致与ALS相关的功能丧失，导致血管生成和运动神经元保护失败。此外,ANG突变有时与其他因素的变体相结合，从而增强ALS效应。然而,天然ANG酶的活性应该很好地平衡，而不是过度,避免可能的有害影响。考虑到这些血管生成核糖核酸酶在许多细胞过程中的相互作用，这篇综述旨在刺激进一步的研究，以更好地阐明ANG和/或RNase4基因突变的后果，为了实现早期诊断,可能,对ALS的成功治疗。
