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。这些神经元的丧失与神经退行性疾病有关，如帕金森病和其他疾病。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谜。我们假设功能障碍的早期事件发生在多巴胺释放位点，起源于突触前蛋白质静止和涉及不同清除系统的膜运输途径的紊乱。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谷氨酸突触的清除机制。有了这些信息，我们将研究多巴胺能开关蛋白停滞的膜运输过程及其在维持突触前健康中的作用。为此，我们确定了三个主要目标：(i)识别和表征多巴胺能钮扣突触前蛋白质静止的局部调节因子；（ii）确定蛋白质稳态效应（共）释放特性和多巴胺能释放位点附近超微结构的变化；（iii）研究多巴胺能（DA）钮扣的病理机制，并验证增强局部监视和突触前蛋白清除的条件可能具有神经保护作用的假设。

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.