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: 7678554
• 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/7678554
• 关键词: Actins; Address; Animals; Anxiety; Behavior; Behavior Control; Behavioral; Biochemical; Biological Assay; Brain; Catabolism; Cell membrane; 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; Human Chromosomes; Impaired cognition; Individual; Ion Channel; Laboratories; Learning; Life; Link; Lipids; Long-Term Potentiation; Mediating; Membrane Protein Traffic; Mental Retardation; Metabolism; Molecular; Mus; Nerve; Neurons; Performance; Phenotype; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Physiological; Play; Presynaptic Terminals; Process; Property; Proteins; Recruitment Activity; Recycling; Relative (related person); Research; Role; Severities; Signal Transduction; Signal Transduction Pathway; Slice; Synapses; Synaptic Vesicles; Synaptosomes; Testing; Transgenic Mice; 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; overexpression; phosphatidylinositol phosphate, PtdIns(4,5)P2; public health relevance; 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（由申请人提供）：唐氏综合症（DS）是智力低下的最常见原因。在DS中，由于存在第三个人类染色体21（HC21），因此综合基因表达会改变。尽管智力低下与HC21的非重叠区域有关，表明其病因的多基因性，但单个基因对该表型的相对贡献尚不清楚。在这里，我们建议Synj1是为DS中心理迟缓贡献的有力候选者。 Synj1编码突触janin 1，一种脑富集脂质磷酸酶，可去磷酸化PIP2。这种富含质膜的脂质调节许多过程，包括信号转导，膜运输和离子通道功能。我们以前的工作表明，PIP2调节突触囊泡（SV）的运输，从而调节神经传递。该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钥匙成分的能力，后者介导了SV的回收。最近，我们的研究表明，PIP2代谢在TS65DN小鼠的大脑中发生了改变，TS65DN小鼠是唐氏综合征的主要遗传模型。通过将Synj1恢复为TS65DN小鼠的疾病，可以挽救该缺陷，并在过表达Synj1的转基因小鼠中概括了基因组（BAC）构建体[TG（SYNJ1）]。源自TG（Synj1）小鼠的原发性皮质神经元在SV运输中显示出缺陷，这些缺陷让人联想到缺乏主要PIP2合成酶的神经元中发现的那些缺陷。此外，TG（SYNJ1）小鼠在莫里斯水迷宫的性能表现出缺陷，这表明由基因剂量不平衡引起的pip2 dyshomeostasis可能导致DS遗传模型中脑功能障碍和认知障碍。基于我们的初步研究，该提案的主要目标将是（i）进一步表征完整突触体中的PIP2代谢缺陷，以及来自DS小鼠模型以及DS的人类胚胎的培养神经元中的培养神经元中的培养神经元； （ii）进一步表征来自TS65DN和TG（Synj1）神经元突触中的生理和超微结构缺陷； （iii）进一步探索PIP2缺乏对转基因小鼠在莫里斯水迷宫范式中的学习能力以及在其他行为任务中的影响。特定表型的发现将促使我们评估在TS65DN背景中恢复Synj1是否会改善这些缺陷。我们预计，我们的研究将确定Synj1的基因剂量失衡是DS遗传模型中发生的脑功能障碍的关键因素，并更好地理解DS中神经生理学缺陷和智力低下的分子基础。公共卫生相关性：唐氏综合症是最常见的智力障碍原因。我们提出的研究的主要目的是进一步表征基因Synj1在该疾病的各种小鼠模型中神经生理和行为缺陷中的影响。该提议基于我们自己的证据，表明Synj1的三体性会导致生化缺陷，即称为PIP2的调节性脂质的缺乏，以及在转基因小鼠模型中学习缺陷。