Role of PIP2 metabolism imbalance in Down Syndrome

PIP2代谢失衡在唐氏综合症中的作用

• 批准号: 7524804
• 负责人: Gilbert Di Paolo
• 金额: $ 34.21万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-25 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7524804
• 关键词: Actins; Address; Animals; Anxiety; Behavior; Behavior Control; Behavioral; Biochemical; Biological Assay; Brain; Catabolism; Cell membrane; Chromosome Pairing; Chromosomes, Human, Pair 21; Clathrin; Cognitive deficits; Collaborations; Complement; Defect; Development; Disease; Down Syndrome; Dyes; Embryo; Endocytosis; Enzymes; Etiology; Exhibits; Functional disorder; Gene Dosage; Gene Expression; Genes; Genetic; Genetic Models; Genomics; Goals; Hippocampus (Brain); Human; Impaired cognition; Individual; Ion Channel; Laboratories; Learning; Life; Link; Lipids; Long-Term Potentiation; Mediating; Membrane Protein Traffic; Mental Retardation; Metabolism; Molecular; Mus; Nerve; Neurons; Numbers; Performance; Phenotype; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Physiological; Play; Presynaptic Terminals; Process; Property; Protein Overexpression; Proteins; Public Health; Rate; Recruitment Activity; Recycling; Relative (related person); Research; Role; Severities; Signal Transduction; Signal Transduction Pathway; Slice; Synapses; Synaptic Vesicles; Synaptosomes; Testing; Transgenic Mice; Transgenic Organisms; Transmission Electron Microscopy; Trisomy; Variant; Work; base; conditioned fear; defined contribution; disability; fluorescence imaging; in vivo; morris water maze; mouse Ts65Dn; mouse model; neurophysiology; neurotransmission; phosphatidylinositol phosphate, PtdIns(4,5)P2; synaptic function; synaptojanin; tool; trafficking; uptake

DESCRIPTION (provided by applicant): Down syndrome (DS) is the most common cause of mental retardation. In DS, integrated gene expression is altered due to the presence of a third copy of human chromosome 21 (HC21). Although mental retardation has been linked to non-overlapping regions of HC21, indicating the multigenicity of its etiology, the relative contribution of single genes to this phenotype is unknown. Here we propose that Synj1 is a strong candidate for contributions to mental retardation in DS. Synj1 encodes synaptojanin 1, a brain- enriched lipid phosphatase that dephosphorylates PIP2. This plasma membrane-enriched lipid regulates many processes, including signal transduction, membrane trafficking and ion channel function. Our previous work has shown that PIP2 regulates synaptic vesicle (SV) trafficking and thereby, neurotransmission. This property is largely due to the ability of this lipid to recruit to the plasma membrane key components of the endocytic machinery, which mediates the recycling of SVs. More recently, our studies have revealed that PIP2 metabolism is altered in the brain of Ts65Dn mice, the major genetic model of Down syndrome. This defect is rescued by restoring Synj1 to disomy in Ts65Dn mice and it is recapitulated in transgenic mice overexpressing Synj1 from a genomic (BAC) construct [Tg(Synj1)]. Primary cortical neurons derived from Tg(Synj1) mice show defects in SV trafficking that are reminiscent of those found in neurons lacking a major PIP2-synthesizing enzyme. Additionally, Tg(Synj1) mice exhibit deficits in performance of the Morris water maze, suggesting that PIP2 dyshomeostasis caused by gene dosage imbalance for Synj1 may contribute to brain dysfunction and cognitive disabilities in genetic models of DS. Based on our preliminary studies, the main goals of this proposal will be (i) to further characterize PIP2 metabolism defects in intact synaptosomes and in cultured neurons from the cortex of DS mouse models as well as of human embryos with DS; (ii) to further characterize physiologic and ultrastructural defects in synapses from Ts65Dn and Tg(Synj1) neurons; and (iii) to further explore the impact of PIP2 deficiency on the learning ability of transgenic mice in the Morris water maze paradigm as well as in other behavioral tasks. The discovery of specific phenotypes will prompt us to assess whether restoring Synj1 to disomy in the Ts65Dn background ameliorates these defects. We anticipate that our studies will identify gene dosage imbalance for Synj1 as a key factor in brain dysfunction occurring in genetic models of DS and provide a better understanding of the molecular basis underlying neurophysiological deficits and mental retardation in DS. PUBLIC HEALTH RELEVANCE: Down syndrome is the most common cause of mental retardation. The main goal of our proposed research is to further characterize the implication of a gene, SYNJ1, in neurophysiological and behavioral deficits in various mouse models of this disorder. This proposal builds on our own evidence showing that the trisomy of SYNJ1 causes a biochemical defect, i.e. the deficiency of a regulatory lipid called PIP2, and learning deficits in a transgenic mouse model.

描述(申请人提供)：唐氏综合症(DS)是最常见的精神发育迟滞原因。在DS中，由于人类21号染色体(HC21)的第三个拷贝的存在，整合基因的表达发生了变化。虽然智力低下与HC21的非重叠区域有关，表明其病因是多基因的，但单基因对该表型的相对贡献尚不清楚。在这里，我们认为Synj1是导致DS患者精神发育迟滞的有力候选基因。Synj1编码Synaptojanin 1，这是一种富含大脑的脂肪磷酸酶，可以使PIP2去磷酸化。这种富含质膜的脂质调节许多过程，包括信号转导、膜转运和离子通道功能。我们以前的工作表明，PIP2调节突触小泡(SV)的运输，从而调节神经传递。这一特性在很大程度上是由于这种脂质能够募集到内吞机械的质膜关键组件，而质膜关键组件介导了SVS的循环。最近，我们的研究发现，PIP2代谢在Ts65Dn小鼠的大脑中发生了变化，Ts65Dn小鼠是唐氏综合症的主要遗传模型。这一缺陷可以通过在Ts65Dn小鼠中将Synj1恢复到二体来修复，并在从基因组(BAC)结构[TG(Synj1)]过度表达Synj1的转基因小鼠中重现。来自TG(Synj1)小鼠的原代皮质神经元在SV运输中显示出缺陷，这与在缺乏主要PIP2合成酶的神经元中发现的缺陷相似。此外，TG(Synj1)小鼠在Morris水迷宫中表现出行为缺陷，提示Synj1基因剂量失衡导致的PIP2动态平衡失调可能是DS遗传模型中脑功能障碍和认知障碍的原因之一。基于我们的初步研究，这项建议的主要目标将是：(I)进一步鉴定PIP2代谢缺陷在完整突触体和DS小鼠模型以及人类DS胚胎大脑皮质中的代谢缺陷；(Ii)进一步鉴定Ts65Dn和Tg(Synj1)神经元突触的生理和超微结构缺陷；以及(Iii)进一步探讨PIP2缺陷对转基因小鼠在Morris水迷宫范式和其他行为任务中学习能力的影响。特定表型的发现将促使我们评估在Ts65Dn背景中将Synj1恢复为二体是否可以改善这些缺陷。我们预计，我们的研究将确认Synj1基因剂量失衡是DS遗传模型中发生脑功能障碍的关键因素，并为更好地理解DS神经生理缺陷和智力低下的分子基础提供依据。公共卫生相关性：唐氏综合症是导致精神发育迟滞的最常见原因。我们提出的研究的主要目标是进一步表征SYNJ1基因在这种疾病的各种小鼠模型中的神经生理和行为缺陷中的意义。这一建议基于我们自己的证据，表明SYNJ1的三体导致了一种生化缺陷，即一种名为PIP2的调节性脂质的缺乏，以及转基因小鼠模型中的学习障碍。