Maintaining presynaptic function in dopaminergic synapses

中脑多巴胺能神经元在大脑中具有重要的功能，包括调节运动功能、动机、决策和奖励。这些神经元的丢失与神经退行性疾病有关，如帕金森病等。多巴胺能神经元对变性高度敏感的原因在很大程度上仍然是个谜。我们推测，早期事件的功能障碍发生在多巴胺的释放网站，并起源于干扰突触前蛋白质稳态和膜运输途径，涉及不同的清除系统。为了验证这一假设，我们将使用遗传学，电生理学和细胞成像工具和技术，我们已经成功地应用于研究清除机制在突触。有了这些，我们将调查膜运输过程中潜在的蛋白质在多巴胺能终扣和它们在维持突触前健康的作用。为此，我们确定了三个主要目标：（i）确定和表征多巴胺能终扣突触前蛋白质稳态的局部调节因子;（ii）确定蛋白质稳态的变化如何影响多巴胺能释放位点附近的（共）释放特性和超微结构;（iii）研究多巴胺（DA）能神经元的病理机制终扣和测试的假设，即条件下，提高当地的监督和清除突触前蛋白可以神经保护。

Midbrain dopaminergic neurons have important functions in the brain, including modulation of motor functions, motivation, decision-making and reward. Loss of these neurons is associated with neurodegenerative disorders, such as Parkinson’s disease and others. The reasons for the high susceptibility of dopaminergic neurons to degeneration are still largely enigmatic. We hypothesize that early events of dysfunction take place at dopamine release sites and originate from disturbed presynaptic proteostasis and membrane trafficking pathways involving different clearance systems. To test this hypothesis, we will use genetic, electrophysiological and cellular imaging tools and techniques that we have successfully applied to study clearance mechanisms at glutamatergic synapses. With those in hand, we will investigate membrane trafficking processes underlying proteostasis at dopaminergic boutons and their role in maintaining presynaptic health. To this end, we have defined three major aims: (i) to identify and characterize the local regulators of presynaptic proteostasis in dopaminergic boutons; (ii) to define how changes in proteostasis effect (co-)release properties and ultrastructure near dopaminergic release sites; and (iii) to study pathological mechanisms in dopaminergic (DA) boutons and test the hypothesis that conditions that enhance local surveillance and clearance of presynaptic proteins can be neuroprotective.