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。神经递质储存在称为突触囊泡（SVs）的神经元内的小球形隔室中。当神经元交流时，SVs与神经元外表面融合，导致神经递质释放。在这种情况发生后，sv会改变并重新充满神经递质。SV重组有多种机制，其中一种被称为活性依赖性大体积内吞作用（ADBE）。我们已经确定了一些控制神经元内ADBE的分子，其中之一是钙调磷酸酶。钙调磷酸酶修饰一种叫做动力蛋白I的酶来刺激ADBE，而ADBE则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量产生引起的。其中两种分子，RCAN1和DYRK1A预计会干扰钙调磷酸酶依赖的动力蛋白i的修饰，这意味着它们也可能干扰ADBE。与此一致的是，退行性椎体滑移患者和小鼠的大脑过量产生与退行性椎体滑移相似的分子补体，其外观与通过停止钙调神经磷酸酶活性来抑制ADBE的神经元非常相似。因此，该应用的总体假设是，DS的症状是动力蛋白I功能失调导致ADBE缺陷的结果。应用程序中概述的项目将通过监测增加或减少神经元中RCAN1和DYRK1A水平对动力蛋白I功能和ADBE的影响来验证这一假设。除了单独观察这些分子外，我们还将确定ADBE和动力蛋白I在从所有DS相关分子补体增加的小鼠中提取的神经元中是否正常发挥作用。本应用程序将系统地研究dynamin I函数、ADBE和DS之间的联系。如果能够证明退行性痴呆中出现的部分或全部脑功能下游缺陷是动力蛋白I或ADBE功能失调的结果，这将为对抗这种疾病的症状提供一个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治疗方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.