Chromogranin A promotes the pathological conversion of α-synuclein at the synapse in Parkinson's disease.

α-Synuclein (αSyn) aggregation is a prominent hallmark of Parkinson's disease (PD), yet the initial cellular mechanisms are not well understood. In this study, we show that a single day of αSyn preformed fibril (PFF) administration leads to prominent localization of phosphorylated αSyn (p-αSyn) within the pre-synapse of primary neurons. Overexpressing chromogranin A (CgA), which is found in large dense-core vesicles (LDCVs), enhances αSyn aggregation in various neuronal and PD mouse models. Subsequently, by incubating αSyn with CgA, we create a unique strain of fibrils displaying smaller length, stronger resistance to proteolytic digestion, and higher amyloidogenic properties compared to conventional αSyn fibrils. Additionally, CgA knockout alleviates dendritic spine loss and synaptic dysfunction induced by αSyn PFF and slows down the spread of pathological inclusions in vivo. Collectively, our findings demonstrate how the intra-vesicular matrix protein CgA triggers and facilitates early seeding events leading to subsequent toxicity caused by αSyn pathology.