Maintaining presynaptic function in dopaminergic synapses

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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.