Extended coverage of human serum glycosphingolipidome by 4D-RP-LC TIMS-PASEF unravels association with Parkinson’s disease

Huong Giang Vo, Gabriel Gonzalez-Escamilla, Daniela Mirzac, Lilia Rotaru, Damian Herz, Sergiu Groppa and Laura Bindila ()
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Huong Giang Vo: University Medical Center
Gabriel Gonzalez-Escamilla: University Medical Center
Daniela Mirzac: University Medical Center
Lilia Rotaru: Diomid Gherman Institute of Neurology and Neurosurgery
Damian Herz: University Medical Center
Sergiu Groppa: University Medical Center
Laura Bindila: University Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract Glycosphingolipids (GSLs) are important targets in immune, infectious, lysosomal storage diseases, cancer, and neurodegenerative diseases. Circulatory GSLs profiling in clinical samples is restricted by the lack of mid- and high-throughput analytical methods and deep coverage of long-chain sialylated glycosphingolipidome. We present a 4-dimensional (4D)-glycosphingolipidomics platform for routine glycosphingolipidome profiling encompassing: extraction and fractionation of sialylated GSLs with 3 to 15 monosaccharides, neutral GSLs and sulfatides; µL-flow reversed-phase LC-TIMS-PASEF MS analysis; semi-quantification strategy adapted for fractionated glycosphingolipidome, and referential CCS, RT, and m/z values for GSLs annotation. 4D-glycosphingolipidomics of human serum reveals a high structural heterogeneity, amounting to 376 GSLs: 159 GSLs of ganglio- and neolacto-series, 145 neutral GSLs and 72 sulfatides. Here we demonstrate the platform’s utility for clinical profiling of Parkinson’s disease (PD) sera. 41 neolacto- and ganglio-species discriminate PD patients from controls and 14 GSLs differentiate sex subgroups, laying the foundation for further functional GSL studies with PD.

Date: 2025
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DOI: 10.1038/s41467-025-59755-6

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