Molecular Interplay of Endocytic Proteins

Project summary Synaptic vesicle endocytosis plays a crucial role in sustaining effective neurotransmission and supporting neural circuit stability. Disruptions in this process can weaken synaptic signaling, contributing to neurological disorders such as Parkinson's disease, Down syndrome, and epilepsy. Two proteins that play key roles in synaptic vesicle recycling are synaptojanin and endophilin. Despite their established roles, the molecular mechanisms governing their coordinated action at synapses remain poorly understood. Preliminary findings from our large-scale genetic screen revealed intriguing mutations in synaptojanin that enable it to function independently of endophilin. This discovery suggests that synaptic deficits in endophilin-null mutants arise from dysregulation of synaptojanin, as function is nearly fully restored by specific synaptojanin mutations. Our results point to a novel regulatory mechanism for synaptojanin, focusing on its membrane interactions rather than solely on protein-protein interactions with endophilin's SH3 domain. In this project, we will investigate the functional implications of these mutations on synaptojanin's role at the synapse. We hypothesize that mutant synaptojanin acquires enhanced membrane-remodeling properties, enabling it to support synaptic vesicle endocytosis without reliance on the membrane-bending protein endophilin. To explore this, we propose to examine how these mutations impact synaptic physiology in absence of endophilin. We will then investigate the underlying biochemical mechanisms that coordinate the actions of synaptojanin and endophilin. Finally, we will evaluate how these mutations affect synaptic function across different life stages, particularly in aging animals. By uncovering the mechanisms that allow synaptojanin to bypass the need for endophilin, this research is expected to reshape our understanding of endocytic protein coordination and provide new insights into synaptic function, with important implications for neurological health.