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

阿尔茨海默病中蛋白磷酸酶 2A 的结构和分子决定因素

• 批准号: 10286189
• 负责人: Goutham Narla
• 金额: $ 25.97万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286189
• 关键词: Alzheimer' s Disease; Biological; Cell Proliferation; Chemicals; Clinic; Complex; Development; Disease; Drug Industry; Equilibrium; Family; Goals; Holoenzymes; KRAS2 gene; Libraries; Malignant Neoplasms; Malignant neoplasm of lung; Microtubules; Molecular; Mutation; Parents; Parkinson Disease; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Property; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Regulation; Signal Pathway; Structure; Therapeutic; Toxic effect; Tumor Suppressor Proteins; base; combat; human disease; inhibitor/antagonist; kinase inhibitor; lung cancer cell; mutant; nervous system disorder; novel strategies; response; small molecule; tau Proteins; tau aggregation; tau-1; tool; tumor; tumor growth

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.

摘要：蛋白质磷酸化是最常见、研究最多的翻译后修饰。 一般来说，激酶激活信号通路，而磷酸酶则充当这些通路的“关闭开关”。 在许多人类疾病中，这种平衡偏向激酶过度激活和/或磷酸酶抑制。 过度磷酸化活性的增强是许多疾病中的常见现象，例如增殖（在本例中） 癌症）不受磷酸酶抑制的抑制，导致细胞快速增殖和肿瘤生长。 同样，在阿尔茨海默氏病的情况下，激酶与磷酸酶的活性比率是倾斜的，因此 微管 tau 蛋白的磷酸化净增加，聚集成原纤维。 阿尔茨海默病和其他神经系统疾病（包括帕金森病）的标志。 激酶活性在许多疾病中通常都会增加，包括癌症和阿尔茨海默病，激酶 不幸的是，抑制剂最近被开发为治疗方法。 调节信号通路、无法选择性地靶向独特的激酶以及与相关的毒性 这种方法在激酶抑制剂的开发及其临床应用方面进展有限。 理论上，磷酸酶激活剂应该具有类似的治疗潜力来纠正 激酶：疾病状态下的磷酸酶活性然而，“激活剂”的开发通常要多得多。 因此，磷酸酶，包括 PP2A 家族的磷酸酶，长期以来一直存在。 被视为制药行业“不可成药”的目标，这种模式最近已被克服。 随着我们和其他人开发出稳定磷酸酶复合物的小分子，我们采用了新策略 重新激活他们的活动并对抗疾病在这个补充提案中，我们寻求扩展小说。 我们成功开发了重新激活 PP2A 磷酸酶来对抗癌症的策略， 重新激活 PP2A 磷酸酶以对抗阿尔茨海默病的类似策略。