PP2A in Neurodevelopmental Disorders

PP2A 在神经发育障碍中的作用

• 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
• 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

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.

项目摘要/摘要 神经发育障碍，包括智力残疾、自闭症、青少年顽固性癫痫，以及 精神分裂症具有很高的社会经济影响，但对其病因却知之甚少。近期较大规模 测序工作发现新基因突变是神经发育障碍的主要原因。大多数De Novo突变出现在父亲的生殖系中，使突变的精原细胞在什么地方具有生长优势 被称为“自私的精原选择”。 蛋白磷酸酶2(PP2A)是一种主要的丝氨酸/苏氨酸磷酸酶，是已知的生长和生长调节因子。 分化和疑似肿瘤抑制因子。催化(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的50个亚基组合中， 可能具有不同的本地化、底物和调节机制。新基因突变的激增 自2015年以来发现的PP2A定义了两类新的常染色体显性智力低下。最多的 普通型是由12个PP2A调节亚单位基因之一的反复错义突变引起的， PPP2R5D是其产物B‘，主要存在于人的睾丸和脑中。相同的从头开始的PPP2R5D 突变会导致人类过度生长，这是一种通常与智力残疾和自闭症相关的综合征。 这一探索性的建议试图确定反复发生从头突变的分子机制。 PPP2R5D(B‘)可引起神经发育障碍。因为有些神经发育障碍 可逆的，我们的结果可能导致新的药理干预。以我们出版的作品为依据 在发现智力低下的PP2A突变之前，我们假设从头开始的突变在 PPP2R5D通过一种新的功能改变机制导致神经发育障碍。具体来说，我们 提示在酸性底物结合表面引入碱性氨基酸可以改变PP2A底物 特异性，以损害一些和有利于其他去磷酸化事件。这反过来可能会增强 生长/增殖信号通路高于那些介导细胞周期退出、分化和 形态发生。为了解决这一假设，这一提议的两个目标将描绘出共识序列 对于野生型和突变型PP2A酶的去磷酸化，用定量的方法鉴定它们的细胞底物 磷酸基因组学，并揭示神经元发育的细胞模型中的表型。基本见解 这一提议有望为新的患者衍生细胞模型、动物模型、诊断 测试，以及最终针对神经发育障碍的PP2A靶向治疗。