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Synaptic dysfunction is an early hallmark of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, and may be driven by phase separation and aggregation of proteins such as alpha-synuclein (aSyn), tau, and huntingtin. Our project used super-resolution imaging, biochemical assays, and proteomics to study how these proteins are released (via exosomes or exo/endocytosis) and how they disrupt synaptic function. Protein-specific differences in release and spreading were identified, and exposure to pathological aSyn species was found to alter synaptic protein networks, especially factors involved in vesicle cycling, and to reduce neuronal firing. A novel cell model forcing aSyn–synphilin-1 co-aggregation enabled mapping of aggregate interactions with organelles, and a PD-linked SNCA G14R mutation was found to modify aSyn aggregation and membrane binding. Building on these findings, the next funding period will define the molecular architecture of aSyn aggregates, test key candidate proteins on vesicle recycling and activity, and relate aSyn species to synaptic function.