Role of Phosphoinositide Imbalance in Down Syndrome

描述(申请人提供)：唐氏综合症(DS)是导致精神发育迟滞(MR)的最常见原因。在DS中，由于21号染色体第三拷贝(HC21)的存在，整合基因的表达发生了变化，导致三体基因的过度表达。虽然MR与HC21的非重叠区域相关联，表明其病因的多基因，但单基因对该表型的相对贡献尚不清楚。在此，我们提出SYNJ1是DS中MR贡献的有力候选者。SYNJ1编码突触素1，一种富含脑磷脂的磷酸酶，负向调节磷脂酰肌醇-4，5-二磷酸(PIP2)的水平。这种脂质在细胞中具有多效性作用，如信号、细胞器运输和肌动蛋白动力学。在神经末梢，PIP2调节突触小泡的运输，因为它能够将胞外和胞内机制的关键成分招募到质膜上。我们最近在小鼠身上的遗传学研究为突触素1在突触小泡循环中的作用提供了强有力的证据，这一过程涉及到网状蛋白介导的内吞作用。此外，我们还发现，大脑中主要的PIP2合成酶的缺乏也损害了突触小泡的运输。有趣的是，我们在部分三体21(Ts65Dn)小鼠模型上的初步工作显示，这些动物的大脑中PI(4，5)P2水平较低。因此，我们推测由SYNJ1过度表达引起的PIP2代谢失衡可能导致DS患者突触囊泡运输缺陷。我们还假设这些缺陷可能导致高级大脑功能的缺陷，如先生。为了验证这些假设，我们将研究部分三体小鼠的PIP2代谢、突触小泡运输和学习表现，并评估使用SYNJ1基因敲除小鼠恢复SYNJ1基因二体后Ts65Dn小鼠的表型的潜在改善。最后，我们将描述过度表达SYNJ1的小鼠的特征，以测试仅SYNJ1的基因剂量失衡是否概括了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.