PP2A in Neurodevelopmental Disorders

PP2A 在神经发育障碍中的作用

基本信息

批准号：
9332781
负责人：
STEFAN STRACK
金额：
$ 22.88万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-15 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9332781
关键词：
Address Adolescent Affinity Amino Acids Animal Model Antibodies Autistic Disorder Basic Amino Acids Binding Binding Sites Biochemical Biological Assay Cell Cycle Cell Line Cell model Child Consensus Sequence Deltastab Diagnosis Diagnostic Procedure Diagnostic tests Differentiation and Growth Disease Embryo Enzyme-Linked Immunosorbent Assay Enzymes Etiology Event Fathers Future Genes Genetic Growth Growth Factor Growth and Development function Holoenzymes Human Human Cell Line Impairment Intellectual functioning disability Intervention Label Large-Scale Sequencing Lead Libraries Link Macrocephaly Malignant Neoplasms Mammalian Cell Mediating Mental Retardation Mentally Disabled Persons Missense Mutation Molecular Morphogenesis Mutate Mutation Neurodevelopmental Disorder Neuronal Differentiation Neurons Normal Cell PC12 Cells PPP2R5B gene PPP2R5D gene PTEN protein Parents Paternal Age Patients Peptide Library Peptides Pharmacology Phenotype Phosphoric Monoester Hydrolases Phosphotransferases Point Mutation Protein Dephosphorylation Protein phosphatase Proteins Proteome Publishing Recurrence Role Schizophrenia Seizures Signal Pathway Signal Transduction Site Spermatogonia Substrate Specificity Surface Syndrome Techniques Testing Testis Brain Touch sensation Tumor Suppressor Proteins Work age effect base cancer risk cell type exome sequencing genetic disorder diagnosis genome editing genome-wide insight mutant neuron development novel protein phosphatase inhibitor-2 scaffold small molecule socioeconomics sperm cell stem targeted treatment tumor

项目摘要

Project Summary / Abstract Neurodevelopmental disorders including intellectual disability, autism, juvenile intractable seizures, and schizophrenia have high socioeconomic impact, yet poorly understood etiologies. Recent large scale sequencing efforts identified de novo mutations as a major cause of neurodevelopmental disorders. Most de novo mutations arise in the paternal germline to confer a growth advantage to mutant spermatogonia in what has been termed “selfish spermatogonial selection”. Protein phosphatase 2 (PP2A), one of the major Ser/Thr phosphatases is a known regulator of growth and differentiation and a suspected tumor suppressor. A trimeric enzyme of catalytic (C), scaffolding (A), and variable regulatory subunits (B,B',B''), PP2A can exist in >50 subunit combinations in mammalian cells, presumably with distinct localization, substrates, and regulatory mechanisms. A surge of de novo mutations in PP2A uncovered since 2015 defined two new classes of autosomal-dominant mental retardation. The most common class is caused by recurrent missense mutations in one of the 12 PP2A regulatory subunit genes, PPP2R5D, the product of which, B' predominates in human testes and brain. The same de novo PPP2R5D mutations cause human overgrowth, a syndrome commonly associated with intellectual disability and autism. This exploratory proposal seeks to identify molecular mechanisms by which recurrent de novo mutations in PPP2R5D (B') cause neurodevelopmental disorders. Because some neurodevelopmental disorders are reversible, our results may lead to new pharmacological interventions. Predicated by our published work predating the discovery of PP2A mutations in mental retardation, we hypothesize that de novo mutations in PPP2R5D cause neurodevelopmental disorders by a novel change-of-function mechanism. Specifically, we suggest that basic amino acids introduced into an acidic substrate-binding surface alter PP2A substrate specifity to impair some and favor other dephosphorylation events. This in turn may enhance growth/proliferative signaling pathways over those that mediate cell cycle exit, differentiation, and morphogenesis. To address this hypothesis, the two aims of this proposal will delineate consensus sequences for dephosphorylation by wild-type and mutant PP2A enzymes, identify their cellular substrates by quantitative phosphoproeomics, and uncover phenotypes in cell models of neuronal development. Fundamental insights from this proposal are expected to pave the way for new patient-derived cell models, animal models, diagnostic tests, as well as ultimately for PP2A-targeted therapies of neurodevelopmental disorders.

项目概要/摘要神经发育障碍，包括智力障碍、自闭症、青少年顽固性癫痫发作和精神分裂症具有很高的社会经济影响，但最近大规模的病因尚不清楚。测序发现从头突变是神经发育障碍的主要原因。父系种系中出现新突变，赋予突变精原细胞生长优势被称为“自私的精原细胞选择”。蛋白磷酸酶 2 (PP2A) 是主要的 Ser/Thr 磷酸酶之一，是已知的生长和发育调节因子。分化和疑似肿瘤抑制因子的三聚酶（C）、支架（A）和可变调节亚基（B、B'、B''），PP2A 可以存在于哺乳动物细胞中 > 50 个亚基组合中，可能具有不同的定位、底物和调控机制。自 2015 年以来发现的 PP2A 定义了两种新的常染色体显性智力障碍。常见类别是由 12 个 PP2A 调节亚基基因之一的反复错义突变引起的， PPP2R5D，其产物B'在人体测试和大脑中占主导地位同样是从头PPP2R5D。突变会导致人类过度生长，这是一种通常与智力障碍和自闭症相关的综合症。该探索性提议旨在确定复发性从头突变的分子机制。 PPP2R5D (B') 导致神经发育障碍因为某些神经发育障碍是。是可逆的，我们的结果可能会导致新的药物干预措施。在发现精神发育迟滞的 PP2A 突变之前，我们捕获了 PPP2R5D 通过一种新的功能改变机制引起神经发育障碍。表明将碱性氨基酸引入酸性底物结合表面会改变 PP2A 底物特异性损害某些去磷酸化事件并有利于其他去磷酸化事件，这反过来可能会增强。生长/增殖信号通路优于那些介导细胞周期退出、分化和为了解决这个假设，该提案的两个目标将描述共有序列。对于野生型和突变型 PP2A 酶的去磷酸化，通过定量鉴定其细胞底物磷酸蛋白质组学，并揭示神经发育细胞模型的表型。该提案预计将为新的患者来源细胞模型、动物模型、诊断铺平道路测试，以及最终针对神经发育障碍的 PP2A 靶向治疗。