Glycomic Profiling Reveals Enhanced Sialylation and Plasma-Derived Fibrinogen Accumulation in the Parkinson's Disease...

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra, a key component of the basal ganglia. The cerebellum, which supports motor learning and cognition and forms a functional network with the basal ganglia, has been associated with both motor and non-motor symptoms of PD. N-glycosylation has been linked to neurodegeneration and alterations in cerebellar neuroimmune and synaptic regulation; however, the structural characteristics of cerebellar N-glycans remain unclear. In this study, we employed a comprehensive liquid chromatography (LC)-quadrupole-Orbitrap-tandem mass spectrometry (MS/MS)-based glycoproteomic approach to characterize N-glycans and N-glycopeptides in postmortem cerebellar tissues from neurologically normal (NM) and PD brains. Forty-two N-glycans were structurally identical but quantitatively distinct, with PD exhibiting increased sialylation (A2G2S2, A2G2S1, A2G1S1) and decreased mannosylation (M5). Glycoproteomic analysis revealed 11 N-glycopeptides in PD, six of which were unique to PD. Three PD-specific N-glycopeptides (DLQSLEDILHQVEN₇₈K, N₇₈: N-glycosylation site) bearing increased sialylated N-glycans originated from the γ-chain of plasma fibrinogen. Consistently, fibrinogen was detected exclusively in PD in MS/MS-based proteomics analysis for protein identification. These findings provide the first structural evidence of enhanced sialylation and plasma-derived glycoprotein accumulation in the PD cerebellum, suggesting that aberrant N-glycosylation may contribute to cerebellar dysfunction and potential blood-brain barrier compromise. Our findings offer insights into the molecular feature underlying cerebellar pathology in PD.