Department of Neuroscience and Pharmacology, and Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa 52242, USA.
J Cell Sci. 2021 Jul 1;134(13). doi: 10.1242/jcs.248187. Epub 2021 Jul 6.
Neurodevelopmental disorders (NDDs), including intellectual disability (ID), autism and schizophrenia, have high socioeconomic impact, yet poorly understood etiologies. A recent surge of large-scale genome or exome sequencing studies has identified a multitude of mostly de novo mutations in subunits of the protein phosphatase 2A (PP2A) holoenzyme that are strongly associated with NDDs. PP2A is responsible for at least 50% of total Ser/Thr dephosphorylation in most cell types and is predominantly found as trimeric holoenzymes composed of catalytic (C), scaffolding (A) and variable regulatory (B) subunits. PP2A can exist in nearly 100 different subunit combinations in mammalian cells, dictating distinct localizations, substrates and regulatory mechanisms. PP2A is well established as a regulator of cell division, growth, and differentiation, and the roles of PP2A in cancer and various neurodegenerative disorders, such as Alzheimer's disease, have been reviewed in detail. This Review summarizes and discusses recent reports on NDDs associated with mutations of PP2A subunits and PP2A-associated proteins. We also discuss the potential impact of these mutations on the structure and function of the PP2A holoenzymes and the etiology of NDDs.
神经发育障碍（NDDs），包括智力障碍（ID）、自闭症和精神分裂症，具有很高的社会经济影响，但发病机制仍不清楚。最近，大规模的基因组或外显子测序研究发现了大量的蛋白磷酸酶 2A（PP2A）全酶亚基的新生突变，这些突变与 NDDs 强烈相关。PP2A 负责大多数细胞类型中至少 50%的总 Ser/Thr 去磷酸化，主要以由催化（C）、支架（A）和可变调节（B）亚基组成的三聚体全酶形式存在。PP2A 可以在哺乳动物细胞中存在近 100 种不同的亚基组合，决定了不同的定位、底物和调节机制。PP2A 作为细胞分裂、生长和分化的调节剂已得到充分证实，PP2A 在癌症和各种神经退行性疾病（如阿尔茨海默病）中的作用已被详细综述。本综述总结和讨论了与 PP2A 亚基和 PP2A 相关蛋白突变相关的 NDD 的最新报道。我们还讨论了这些突变对 PP2A 全酶结构和功能以及 NDD 发病机制的潜在影响。
