Parkinson's Disease-Associated Remodeling of Synaptic N-Glycans in the Human Prefrontal Cortex

Parkinson's disease (PD) is characterized by progressive motor and cognitive dysfunction and is associated with synaptic pathology and impaired neurotransmission, including dysfunction of synaptic vesicles (SVs) and presynaptic terminals. However, the role of protein N-glycosylation within synaptic subcellular fractions remains understudied. Here, N-glycomics analysis was performed on synaptosomes and SVs enriched from the prefrontal cortex (PFC) of post-mortem PD and control brains using high-resolution LC-MS/MS. A total of 66 N-glycans were identified in synaptosomes and 68 in SVs, with PD-associated glycomics alterations showing clear fraction-specific patterns. PD synaptosomes exhibited reduced sialofucosylation alongside increased fucosylated and neutral glycans, including altered sialyl Lewis X (sLeX)-bearing structures, suggesting potential involvement in neuroinflammation and aberrant cell signaling. In contrast, PD SVs showed elevated high-mannose and neutral glycans. Isomer-resolved N-glycomics revealed distinct remodeling of glycan isomers in PD, characterized by altered branching, fucosylation, and sialylation in both fractions. Notably, PD synaptosomes displayed shifts toward highly branched fucosylated and sialylated isomers, while PD SVs exhibited changes consistent with impaired glycan maturation. Together, these findings demonstrate that PD induces distinct N-glycan alterations in PFC synaptic fractions, providing new insights into synaptic dysfunction associated with cognitive decline in PD.