Structural and spatial decoding of presynapse formation in situ

• Applicant: Professor Volker Haucke, Ph.D.
• Subject Area: Developmental Neurobiology ; Biochemistry ; Structural Biology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 559304079

Neurotransmission is central to our ability to move and for sensation, memory and cognition. The modulation of synapse strength, e.g. the regulation of synaptic weight within functional neuronal networks by remodeling of synaptic nanoscale architecture and composition is crucial for our ability to learn and for higher brain function. In great contrast to the wealth of knowledge regarding the mechanisms for neurotransmission, how synapses form during development and are remodeled in the mature nervous system has remained one of the enigmas of molecular neuroscience. The proposed project will fill the fundamental knowledge gap in neuroscience how the presynapse is assembled from axonal transport packets. We expect to break new ground by unravelling the nanoscale architecture and molecular composition (e.g. the proteome and lipidome) of the axonal precursor vesicles (PV) that deliver newly synthesized synaptic vesicle (SV) and active zone (AZ) proteins to nascent synapses in human neurons. For example, we expect to answer the question whether SV proteins are pre-assembled into functional units within PVs and where AZ proteins or other non-SV membrane proteins are located on PV membranes. Moreover, we will obtain unprecedented insight into PV remodeling along the presynaptic biogenesis pathway and identify the carriers for axonal transport and delivery of newly synthesized voltage-gated calcium channels (VGCCs). We expect these latter findings to serve as a door opener for the calcium channel field. Given the close links of the machinery for axonal transport with neurological and neuropsychiatric diseases, we further predict our studies to be of fundamental importance for biomedicine. Finally, the project will provide proof-of-principle that organelles of high complexity can be characterized with unprecedented detail by a multidisciplinary integrative structural biology, proteomics, and cell biology approach that combines experimental data with computational modeling.

• DFG Programme: Reinhart Koselleck Projects