synERgy · Organization and function of the axonal Endoplasmic Reticulum

Brain function relies on neurotransmission at synapses, where local increases in calcium trigger the fusion of synaptic vesicles and release of their neurotransmitters. Decades of research yielded detailed knowledge on synaptic vesicles and the individual proteins that mediate neurotransmission. Conversely, we know surprisingly little about the synaptic contribution of the largest organelle in neurons: the Endoplasmic Reticulum (ER). Aberrant alterations in ER shape are, however, associated with many neurologic disorders, highlighting the importance of understanding the role this organelle plays in the neuron. Taking into consideration the mere quantity and range of specialized ER functions such as calcium signalling and lipid synthesis, the neuronal ER has received very little attention. I therefore strive to shed light on the major, unresolved questions of the field, namely what the ER protein composition is in synapses and how the ER contributes to important neuronal functions such as neurotransmission.To dissect ER function in neurons I will first characterize the composition of neuronal ER proteins and identify the key players that regulate ER degradation. Second, I will manipulate ER content, localization and degradation to understand how the ER contributes to neurotransmission and development. Finally, I will investigate the importance of ER and ER degradation for physiological and pathophysiological processes in vivo. To this end, I propose a multidisciplinary approach using advanced imaging techniques, endogenous protein tagging and proteomics to study ER function and its regulated degradation in neurons. These studies will yield innovative fundamental insights into the role of synaptic ER and thereby fill a crucial knowledge gap in neuroscience. Furthermore, they will provide a better understanding and explanation of how defects in ER and ER degradation cause neurodegenerative diseases.