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，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，但对病因的理解不足。最近的大规模 测序工作确定从头突变是神经发育障碍的主要原因。大多数 在父亲种系中出现了Novo突变，以赋予突变体精子的增长优势。 已被称为“自私的精子选择”。 蛋白质磷酸酶2（PP2A），主要的Ser/Thr磷酸酶之一是已知的生长调节剂 分化和可疑的肿瘤抑制剂。催化（C），脚手架（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， 从头突变激增 自2015年以来发现的PP2A定义了两种新类型的常染色体主导智力低下。最多 共同类是由12个PP2A调节亚基基因之一的复发错义突变引起的 PPP2R5D，其乘积在人体测试和大脑中占主导地位。同一NOVO 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。 该探索性建议旨在确定从头突变中复发的分子机制 PPP2R5D（B'I）引起神经发育障碍。因为某些神经发育障碍是 可逆的结果可能会导致新的药物干预措施。由我们发表的工作取决于 在智力低下的PP2A突变之前，我们假设从头突变 PPP2R5D通过一种新的功能变化机制引起神经发育障碍。具体来说，我们 建议引入酸性底物结合表面的碱性氨基酸改变PP2A底物 规格损害了一些并有利于其他去磷酸化事件。反过来可能会增强 介导细胞周期出口，分化和的生长/增殖信号通路 形态发生。为了解决这一假设，该提案的两个目标将描述共识序列 为了通过野生型和突变体PP2A酶去磷酸化，通过定量鉴定其细胞底物 磷酸化组学和神经元发育细胞模型中的表型。基本见解 预计该建议将为新的患者衍生细胞模型，动物模型，诊断铺平道路 测试以及最终针对PP2A靶向的神经发育疾病的疗法。