Aberrant protein phosphorylation in Down Syndrome and activity-dependent bulk endocytosis - a causal link?

脑细胞（神经元）通过释放化学神经递质进行交流。神经递质储存在神经元内称为突触囊泡（SV）的小球形隔室中。当神经元交流时，SV与神经元的外表面融合，引起神经递质释放。在此之后，SV改革并重新充满神经递质。SV可以通过多种机制进行改革，其中之一称为活性依赖性大量内吞作用（ADBE）。我们已经确定了一些控制神经元内ADBE的分子，其中之一是钙调神经磷酸酶。钙调磷酸酶修饰一种称为发动蛋白I的酶以刺激ADBE，而ADBE被其他逆转这种修饰的酶关闭。遗传性疾病唐氏综合症（DS）是由一些关键分子的过度生产造成的。这些分子中的两个，RCAN1和DYRK1A被预测干扰钙调神经磷酸酶依赖的动力蛋白I修饰。这意味着它们也可能干扰ADBE。在协议中，DS患者和小鼠的大脑，过量产生类似的分子补充DS有一个非常相似的神经元，有ADBE抑制停止钙调磷酸酶活性的外观。因此，本申请的总体假设是DS的症状是发动蛋白I功能失调的结果，其导致ADBE缺陷。申请中概述的项目将通过监测增加或减少神经元中RCAN1和DYRK1A的水平对动力蛋白I功能和ADBE的影响来测试这一假设。除了单独观察这些分子外，我们还将确定ADBE和发动蛋白I是否在取自小鼠的神经元中正常发挥功能，这些神经元具有增加的所有DS相关分子的补体。本申请将系统地研究发动蛋白I功能，ADBE和DS之间的联系。如果能够证明在DS中看到的部分或全部脑功能下游缺陷是功能失调的发动蛋白I或ADBE的结果，这将为对抗疾病症状提供令人兴奋的新研究机会。此外，由于已经确定了影响ADBE的药物，因此可以操纵一系列新的和潜在的关键疗法来治疗该疾病的下游后果。

Brain cells (neurones) communicate by releasing chemical neurotransmitters. Neurotransmitters are stored in small spherical compartments within neurones called synaptic vesicles (SVs). When neurones communicate, SVs fuse with the outer surface of the neurone causing neurotransmitter release. After this occurs, SVs reform and are refilled with neurotransmitter. There are multiple mechanisms by which SV can reform and one of them is called activity-dependent bulk endocytosis (ADBE). We have identified some of the molecules that control ADBE inside neurones, one of them being calcineurin. Calcineurin modifies an enzyme called dynamin I to stimulate ADBE, whereas ADBE is switched off by other enzymes that reverse this modification. The genetic disorder Down Syndrome (DS) results from the overproduction of a number of key molecules. Two of these molecules, RCAN1 and DYRK1A are predicted to interfere with the calcineurin-dependent modification of dynamin I. This means that they might also perturb ADBE. In agreement, the brains of both DS patients and mice that overproduce a similar complement of molecules to DS have a very similar appearance to neurones that have had ADBE inhibited by stopping calcineurin activity. Therefore the overall hypothesis of the application is that the symptoms of DS are a result of a dysregulation of dynamin I function which leads to defects in ADBE. The project outlined in the application will test this hypothesis by monitoring the effect of increasing or decreasing the level of either RCAN1 and DYRK1A in neurones on both dynamin I function and ADBE. In addition to looking at these molecules in isolation, we will determine if ADBE and dynamin I function normally in neurones taken from mice that have an increased complement of all DS related molecules. This application will systematically investigate the link between dynamin I function, ADBE and DS. If it can be proven that some or all of the downstream defects in brain function seen in DS are a result of dysfunctional dynamin I or ADBE this will provide an exciting new research opportunity to combat the symptoms of the disease. Furthermore, since drugs that influence ADBE have already been identified, a range of new and potentially key therapeutics could be manipulated to treat the downstream consequences of the disorder.