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: 7886831
• 负责人: Gilbert Di Paolo
• 金额: $ 33.87万
• 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/7886831
• 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，由于人类 21 号染色体 (HC21) 的第三个拷贝的存在，整合的基因表达发生了改变。尽管智力低下与 HC21 的非重叠区域有关，表明其病因学的多基因性，但单个基因对该表型的相对贡献尚不清楚。在这里，我们提出 Synj1 是对 DS 精神发育迟滞做出贡献的有力候选者。 Synj1 编码 synaptojanin 1，这是一种大脑富集的脂质磷酸酶，可使 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、膜运输和离子通道功能。我们之前的工作表明，PIP2 调节突触小泡 (SV) 运输，从而调节神经传递。这一特性很大程度上是由于这种脂质能够招募到内吞机制的质膜关键组件，从而介导 SV 的再循环。最近，我们的研究表明，Ts65Dn 小鼠（唐氏综合症的主要遗传模型）的大脑中 PIP2 代谢发生了改变。通过在 Ts65Dn 小鼠中将 Synj1 恢复为二体性可以挽救该缺陷，并且在从基因组 (BAC) 构建体 [Tg(Synj1)] 过表达 Synj1 的转基因小鼠中重现该缺陷。来自 Tg(Synj1) 小鼠的初级皮质神经元显示出 SV 运输缺陷，这让人想起在缺乏主要 PIP2 合成酶的神经元中发现的缺陷。此外，Tg(Synj1)小鼠在Morris水迷宫中表现出缺陷，这表明Synj1基因剂量不平衡引起的PIP2动态平衡可能导致DS遗传模型中的脑功能障碍和认知障碍。根据我们的初步研究，该提案的主要目标是（i）进一步表征完整突触体和来自 DS 小鼠模型以及 DS 人类胚胎皮层的培养神经元中的 PIP2 代谢缺陷； (ii) 进一步表征 Ts65Dn 和 Tg(Synj1) 神经元突触的生理和超微结构缺陷； (iii)进一步探讨PIP2缺陷对转基因小鼠在Morris水迷宫范式以及其他行为任务中的学习能力的影响。特定表型的发现将促使我们评估在 Ts65Dn 背景下将 Synj1 恢复为二倍体是否可以改善这些缺陷。我们预计我们的研究将确定 Synj1 基因剂量不平衡是 DS 遗传模型中发生脑功能障碍的关键因素，并提供对 DS 神经生理缺陷和智力低下潜在分子基础的更好理解。公众健康相关性：唐氏综合症是智力低下的最常见原因。我们提出的研究的主要目标是进一步表征基因 SYNJ1 在这种疾病的各种小鼠模型的神经生理和行为缺陷中的含义。该提议建立在我们自己的证据之上，该证据表明 SYNJ1 三体性会导致生化缺陷，即称为 PIP2 的调节脂质的缺乏，以及转基因小鼠模型中的学习缺陷。