RG 5228: Membrane trafficking processes underlying presynaptic proteostasis

Neurons are polarized cells with a complex cytoarchitecture. Typically, the number of synapses is huge, their molecular makeup extraordinarily complex, and their distance from the cell body, where most protein synthesis occurs, can be enormous. Because neurons are both postmitotic and long-lived, maintaining the integrity of their proteome is of particular importance. Several hundred different proteins can be found in forebrain synapses and this complex proteome creates a unique situation with respect to the molecular dynamics of protein exchange, in particular at the presynapse. Due to synaptic transmission, local membrane exchange is exceptionally high at axonal terminals and accordingly the presynapse represents a region of high energy demand and highly active membrane dynamics. How protein turnover is regulated in axons and axon terminals, and whether this occurs locally (i.e. at the synapse) or in the soma is a key cell biological question. Currently there is a surprising paucity of data on necessities for, and mechanisms of protein replacement at presynapses. Gaps in our knowledge concern: which degradative pathways are involved, how proteins are sorted for certain degradative mechanisms, how sorting itself is accomplished, how different pathways contribute to the presynaptic proteome, which signals direct proteins into a given pathway, how synaptic activity affects degradation, how cross-talk is regulated, and which presynaptic sensor mechanisms identify protein 'damage'. We also lack a thorough understanding on how the different modes of protein degradation interconnect with the need for protein replenishment, i.e. protein translation. It is thus timely to address this long list of unresolved issues and open questions. To accomplish this goal, we assembled a team of expert synaptic biologists who will contribute different methodologies and competences to the problem of presynaptic proteo?stasis. The Team includes researchers from Berlin, Magdeburg and the Technion in Haifa that (i) cover a broad range of techniques, (ii) are at the technological forefront in molecular neuroscience research, and (iii) display synergistic potential to mark for a super-additive team. In a joint effort our mission will be to break new ground by addressing the following questions: What are the specific contributions of autophagy, proteasome-mediated and endolysomal degradation to presynaptic proteostasis? How are presynaptic function and, importantly, plasticity regulated by autophagy? How is autophagy regulated locally? and, finally, how do non-canonical functions of autophagosomes (e.g. signalling) impact presynaptic development, maintenance and function?