Structural and molecular determinants of protein phosphatase 2A in Alzheimer's Disease

摘要：蛋白质磷酸化是最常见、研究最深入的翻译后修饰。在……里面 一般来说，激酶激活信号通路，而磷酸酶则充当这些通路的“关断开关”。 在许多人类疾病中，这种平衡偏向于激酶过度激活和/或磷酸酶抑制。 过度磷酸化活性增强是许多疾病的共性，如增殖(在这种情况下 癌症)不受磷酸酶抑制，导致细胞快速增殖和肿瘤生长。 类似地，在阿尔茨海默病的情况下，激酶与磷酸酶的活性比率是扭曲的，以至于 微管tau获得了磷酸化的净增加。磷酸化的tau聚集成纤维，这些纤维是 阿尔茨海默氏症和包括帕金森氏症在内的其他神经疾病的特征。因为 在包括癌症和阿尔茨海默氏症在内的许多疾病中，激酶活性普遍升高 最近，抑制剂已被开发为治疗方法。不幸的是， 调节信号通路，不能选择性地以独特的激酶为靶点，以及与 这种方法限制了激酶抑制剂的开发及其在临床上的应用。 从理论上讲，磷酸酶激活剂应该具有类似的治疗潜力，以纠正 激酶：疾病状态下的磷酸酶活性。然而，激活剂的发展通常要多得多 这比开发一种“抑制物”更难。因此，磷酸酶，包括PP2A家族中的那些，长期以来 在制药业中一直被视为“无法下药”的目标。这种模式最近已经被克服了 随着我们和其他人开发出稳定磷酸酶复合体的小分子 以重新激活它们的活动并与疾病作斗争。在这个补充提案中，我们试图扩展小说 我们成功地开发了在抗癌中重新激活PP2A磷酸酶的策略，以 重新激活PP2A磷酸酶以对抗阿尔茨海默病的类似策略。

Abstract: Protein phosphorylation is the most frequent and best studied post-translational modification. In general, kinases activate signaling pathways, whereas phosphatases behave as the “off-switch” of those paths. In many human diseases this balance is skewed toward kinase hyperactivation and/or phosphatase suppression. The enhanced activity of hyperphosphorylation is a commonality in many diseases as proliferation (in the case of cancer) in unchecked with phosphatase suppression, leading to rapid cell proliferation and tumor growth. Similarly, in the case of Alzheimer’s Disease, the kinase-to-phosphatase activity ratio is skewed, such that the microtubule tau gains a net increase in phosphorylation. Phosphorylated tau aggregates into fibrils that are the hallmark of Alzheimer’s Disease and other neurological disorders including Parkinson’s Disease. Because kinase activity is commonly increased in many diseases, including cancer and Alzheimer’s Disease, kinase inhibitors have recently been developed as therapeutic approaches. Unfortunately, the redundancy in kinases in regulating signaling pathways, an inability to selectively target unique kinases, and the toxicity associated with this approach, have limited progress in the development of kinase inhibitors and their use in the clinic. Theoretically, a phosphatase activator should have a similar therapeutic potential in correcting the kinase:phosphatase activity in disease states. However, the development of ‘activators’ is generally much more difficult than developing an ‘inhibitor’. Therefore, phosphatases, including those in the PP2A family, has long been seen as ‘undruggable’ targets in the pharmaceutical industry. This paradigm has recently been overcome with new strategies as we, and others, have developed small molecules that stabilize phosphatase complexes to reactivate their activity and to combat disease. In this supplemental proposal, we seek to expand the novel strategy we have successfully developed in reactivating PP2A phosphatases in combating cancer, to an analogous strategy in reactivating PP2A phosphatases to combat Alzheimer’s Disease.