Good science shows the way. Highlight Commentary on "Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice--a model of familial amyotrophic lateral sclerosis".-猫眼课题宝

好的科学指明了道路。

DOI：

10.1016/j.freeradbiomed.2007.04.011

发表时间：

2007

期刊：

Free radical biology & medicine

影响因子：

7.4

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

Estévez,AlvaroG

肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是运动皮层中的锥体神经元以及脑干和脊髓中的运动神经元的变性。 ALS 无法治愈，患者通常在诊断后 1 至 5 年内死于呼吸衰竭。 ALS 的病因尚不清楚。大多数病例是散发性的，10%的病例是遗传性的（家族性ALS）[1]。 1993 年，抗氧化酶超氧化物歧化酶基因突变与 2-3% 的家族性 ALS 病例有关 [2]。这些报告提出了 ALS 中的氧化应激假说，该假说最初被认为是由功能丧失引起的。不久之后，人们就清楚这些突变导致了功能的获得。突变型SOD获得毒性功能假说的基础是，某些突变型酶具有与野生型SOD相同的活性，缺乏SOD的小鼠不会患上运动神经元疾病，而突变型但野生型SOD转基因小鼠不会患上ALS样疾病[3]。与此同时，在人类 ALS 患者和 ALS 转基因小鼠模型中发现了氧化损伤标志物。尽管解释突变型 SOD 功能增强的氧化假说并未得到普遍接受 [4]，但 ALS 患者和该疾病动物模型中发生氧化的事实是无可争议的 [5]。然而，氧化损伤是否在诱导运动神经元死亡中发挥核心作用，或者是一种没有病理意义的共同现象，仍然未知。这一未知数引起了许多 ALS 研究人员的怀疑，他们认为氧化应激只不过是一种次要现象，在该疾病的发病机制中很少或根本不重要[4]。氧化损伤研究的主要问题是识别氧化损伤的相关靶点。 1995 年，发表了两篇论文，为 ALS 中的氧化应激带来了强大的分析方法的优势 [6, 7]。使用二维凝胶电泳和质谱分析，在 ALS 症状前动物模型中，一种确定了羰基形成 [6]，另一种确定了酪氨酸硝化 [7]。更重要的是鉴定出可能对该疾病的病理学有影响的特定靶蛋白。值得注意的是，Poon 等人鉴定出的氧化蛋白存在于 ALS 人类患者和动物模型的聚集体中 [6]。鉴定出的氧化蛋白之一是 SOD1 本身。 SOD 的氧化会改变其生化特性和金属结合特性。此外，本报告对此前的极端立场采取了更为保守的态度。在这篇出版物中，巴特菲尔德小组讨论了氧化应激如何引起蛋白质聚集，将两个明显不可调和的立场联系起来，更多的是因为研究的态度而不是结果的性质[6]。许多研究人员可能认为这些论文更多的是氧化应激论文；但潘的报告是自由基生物学和医学中下载量较高的论文之一，这一事实表明它也引起了许多其他研究人员的好奇心。似乎做出解释来解释大部分现有结果会吸引人们对继续这些重要调查产生新的兴趣。在这个新的想法和假设被视为最后的“真实”而被拥抱的时代，同时旧的想法和假设被遗忘，甚至

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of pyramidal neurons in the motor cortex and motor neurons in the brain stem and spinal cord. There is not cure for ALS and the patients typically die of respiratory failure between 1 and 5 years after diagnostic. The causes of ALS are unknown. Most of the cases are sporadic and 10% of the cases are hereditary (familial ALS)[1]. In 1993, mutations in the gene of the antioxidant enzyme superoxide dismutase were linked to 2–3% of the cases of familial ALS [2]. These reports lead to the oxidative stress hypothesis in ALS, which was first though to be produced by a loss-of-function. Soon after, it becomes clear that the mutations were responsible for a gain-of-function. The mutant SOD gain of toxic function hypothesis was based in the fact that some mutant enzymes had the same activity than wild type SOD, mice deficient for SOD do not develop motor neuron disease and mice transgenic for mutant, but not to wild type SOD develop an ALS-like disease [3]. At the same time markers of oxidative damage were reported in human ALS patients and transgenic mice models of ALS. Although, the oxidative hypothesis to explain the mutant SOD gain-in-function does not have general acceptance [4], the fact that oxidation occurs in ALS patients and animal models of the disease is incontrovertible [5]. However, whether oxidative damage plays a central role in the induction of motor neuron death, or is a co-phenomenon without pathological implications, remains unknown. This unknown has lead to skepticism in many ALS investigators, which consider oxidative stress no more than a secondary phenomenon of little or no importance in the pathogenesis of the disease [4]. The main problem in the research of oxidant-induced damage has been identifying relevant targets of oxidative damage. In 1995, two papers were publishing that brought the strength of powerful analytical methods to oxidative stress in ALS [6, 7]. One identified carbonyl formation [6] and the other tyrosine nitration [7] in pre-symptomatic animal models of ALS using two-dimension gel electrophoresis and mass spectrometry analysis. More importantly was the identification of specific target proteins with possible implications in the pathology of the disease. Remarkably, the oxidized proteins identified by Poon et al are present in aggregates in human patients and animal models of ALS [6]. One of the oxidized proteins identified was SOD1 itself. Oxidation of SOD changes its biochemical properties and the metal binding properties. In addition, the paper this report takes a more conservative approach on previously extreme positions. In this publication, the Butterfield group discusses how protein aggregation could be caused by oxidative stress, linking two apparently irreconcilable positions, more because of the attitude of the researches than the nature of the results [6]. It is possible that many investigators dismiss these papers as more of those oxidative stress papers; but the fact the Poon’s report is one of the higher download papers from Free Radical Biology and Medicine indicates it has also awaken the curiosity of many other investigators. It seems that making an interpretation that explains much of the available results attract new interest in continue these important investigations. In this era in which new ideas and hypotheses are embraced as the last “true,” while at the same time old ideas and hypotheses are forget, even

Good science shows the way. Highlight Commentary on "Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice--a model of familial amyotrophic lateral sclerosis".

好的科学指明了道路。

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