Role of Phosphoinositide Imbalance in Down Syndrome

描述（由申请人提供）：唐氏综合症（DS）是导致智力迟钝（MR）的最常见原因。在DS中，由于21号染色体（HC21）的第三个拷贝的存在，整合基因表达发生改变，导致三体基因过表达。尽管MR与HC21的非重叠区域有关，表明其病因具有多基因性，但单个基因对这种表型的相对贡献尚不清楚。在这里，我们提出SYNJ1是DS中MR贡献的有力候选。SYNJ1编码synaptojanin 1，这是一种富含大脑的磷酸肌醇磷酸酶，负调节磷脂酰肌醇4,5-二磷酸（PIP2）的水平。这种脂质在细胞中具有多种作用，如信号传导、细胞器运输和肌动蛋白动力学。在神经末梢，由于PIP2能够将胞外和内吞机制的关键成分招募到质膜，因此它调节突触囊泡的运输。我们在小鼠中的遗传研究最近为突触蛋白1在突触囊泡循环中的作用提供了强有力的证据，这一过程涉及网格蛋白介导的内吞作用。此外，我们发现大脑中主要的pip2合成酶的缺乏也会损害突触囊泡的运输。有趣的是，我们对21部分三体（Ts65Dn）小鼠模型的初步研究表明，这些动物大脑中的PI(4,5)P2水平较低。因此，我们假设由SYNJ1过表达引起的PIP2代谢失衡导致DS突触囊泡运输缺陷。为了验证这些假设，我们将研究部分三体小鼠的PIP2代谢、突触囊泡运输和学习表现，并使用SYNJ1基因敲除小鼠在Ts65Dn小鼠中恢复SYNJ1基因后，评估其表型的潜在改善。最后，我们将对过表达SYNJ1的小鼠进行表征，以测试SYNJ1单独的基因剂量失衡是否再现了Ts65Dn小鼠中观察到的任何表型。

DESCRIPTION (provided by applicant): Down syndrome (DS) is the most common cause of mental retardation (MR). In DS, integrated gene expression is altered due to the presence of a third copy of chromosome 21 (HC21), which results in the overexpression of the trisomic genes. Although MR 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 MR in DS. SYNJ1 encodes synaptojanin 1, a brain- enriched phosphoinositide phosphatase that negatively regulates the levels of phosphatidylinositol-4,5-bisphosphate (PIP2). This lipid has pleiotropic roles in cells, such as signaling, organelle trafficking and actin dynamics. In nerve terminals, PIP2 regulates synaptic vesicle trafficking, due to its ability to recruit to the plasmalemma key components of the exocytic and endocytic machineries. Our genetic studies in mouse have recently provided robust evidence for a role of synaptojanin 1 in synaptic vesicle recycling, a process that involves clathrin-mediated endocytosis. Moreover, we have found that the lack of the main PIP2-synthesizing enzyme in the brain also impairs synaptic vesicle trafficking. Interestingly, our preliminary work on a mouse model of partial trisomy 21 (Ts65Dn) has shown lower PI(4,5)P2 levels in the brain of these animals. Therefore, we hypothesize that the imbalance of PIP2 metabolism caused by the overexpression of SYNJ1 produces synaptic vesicle trafficking defects in DS. We also hypothesize that these defects may contribute to deficits of higher brain functions, such as MR. To test these hypotheses, we will study PIP2 metabolism, synaptic vesicle trafficking and learning performances in partial trisomy mice and assess potential ameliorations of the phenotypes after restoring to disomy the SYNJ1 gene in Ts65Dn mice using SYNJ1 knockout mice. Finally, we will characterize mice overexpressing SYNJ1 to test whether gene dosage imbalance for SYNJ1 alone recapitulates any of the phenotypes observed in Ts65Dn mice.