Integrated multi-omics identifies PTGDS-enriched mature oligodendrocyte state remodeling in paraquat-associated Parkinson's disease.

Authors

Yu Zhang, Ruolan Pan, Zhiyu Zhang, Jiahong Lin, Fuli Zheng, Hong Hu, Guangxia Yu, Wenya Shao, Zhenkun Guo, Huangyuan Li, Siying Wu

Published in

Environment international. Volume 217. Pages 110598. Nov 06, 2026. Epub Nov 06, 2026.

Abstract

Paraquat (PQ) is an environmentally relevant herbicide associated with neurotoxicity and Parkinson's disease (PD) risk, yet the key molecular determinants linking PQ exposure to PD and the cellular states in which these alterations occur remain incompletely understood. We integrated network toxicology, human PD transcriptomics, machine learning, single-cell RNA sequencing, spatial transcriptomics, spatial metabolomics, virtual perturbation, model-inferred protein analysis, molecular docking, and tissue validation to characterize PQ-associated molecular and cellular remodeling. Integrating PQ-associated targets with PD-related genes identified 293 candidates, among which prostaglandin D2 synthase (PTGDS) was consistently prioritized by random forest, XGBoost, and LASSO, with its PD-associated expression pattern reproduced across the discovery and independent validation cohorts. Single-cell analysis localized Ptgds expression predominantly to oligodendrocytes and identified two PTGDS-enriched mature oligodendrocyte (MOL) states with PQ-associated compositional patterns. CytoTRACE placed these PTGDS-enriched populations among relatively mature oligodendrocyte states. Functional analyses revealed distinct state-specific programs, with Ptgds⁺Mag⁺ MOL associated with myelin-associated programs, axon ensheathment-related programs, cholesterol metabolism, and lipid transport, whereas Ptgds⁺Il33⁺ MOL was linked to neuron-interaction-related programs, synaptic organization, cell adhesion, and neuron-glia communication. Ligand-receptor inference and spatial analyses supported state-specific changes in neuron-glia communication and spatial relationships. Spatial metabolomics showed significantly increased phosphatidylcholine and sphingomyelin signals in regions with higher inferred representation of Ptgds⁺Mag⁺ MOL states. Virtual Ptgds perturbation and scTranslator-based protein prediction further suggested state-specific myelin-lipid and neuron-interaction programs, while molecular docking provided preliminary structural predictions regarding a potential PQ-PTGDS interaction. Immunofluorescence further confirmed PTGDS localization in mature oligodendrocytes within the substantia nigra. Collectively, these findings identify PTGDS-enriched mature oligodendrocyte states as cellular contexts associated with PQ-related brain remodeling and extend our understanding of PQ neurotoxicity beyond classical neuron-centered mechanisms. This integrative framework provides mechanistic insight into how an environmental neurotoxicant may reshape myelin-lipid homeostasis and neuron-glia interactions in the context of PD-related brain pathology.

PMID:
43002971
Bibliographic data and abstract were imported from PubMed on 10 Nov 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.