Integrated single-cell and bulk transcriptomic profiling identifies mannose metabolism-related biomarkers in Parkinson's disease

Abstract Parkinson's disease (PD) is a major neurodegenerative disorder after Alzheimer's disease, yet the molecular alterations driving its onset and progression remain only partly understood. Although mannose metabolism has been linked to nervous-system dysfunction, its contribution to PD has not been clearly defined. This work aimed to screen PD biomarkers related to mannose metabolism and to characterize their possible biological roles. Bulk transcriptome datasets, single-cell RNA-sequencing data, and clinical validation samples were analyzed together. Candidate biomarkers were filtered through weighted gene co-expression network analysis (WGCNA), differential expression analysis, machine-learning algorithms, and external validation. Functional enrichment, immune-cell deconvolution, drug/compound prediction, and molecular docking were used to infer biomarker-related mechanisms. Single-cell analyses further evaluated cell-specific expression patterns and intercellular communication, and reverse transcription–quantitative polymerase chain reaction (RT-qPCR) was performed for experimental confirmation. The WGCNA procedure defined 684 genes in mannose metabolism-associated modules, while differential expression analysis detected 808 altered genes. After sequential screening, SELENBP1, AK3, and C9orf41 (also termed CARNMT1) were retained as biomarkers. They were enriched in 67, 46, and 63 pathways, respectively, including oxidative phosphorylation. Immune analysis showed significant differences in M0 macrophages, monocytes, and activated natural killer (NK) cells between groups. Docking predicted binding energies of -6.4, -7.1, and -10.5 kcal/mol for SELENBP1-bisphenol A, AK3-bisphenol A, and C9orf41-doxorubicin, respectively. Six cell populations were annotated, and CD8 T cells and CD4 T cells showed relatively high biomarker expression and were selected as key cells. B cell-to-CD8 T cell and B cell-to-granulocyte-macrophage progenitor (GMP) communication was observed only in PD samples. RT-qPCR confirmed significant downregulation of SELENBP1, AK3, and C9orf41 in PD samples. SELENBP1, AK3, and C9orf41 were screened as PD-related mannose metabolism biomarkers and may provide candidate molecules for future mechanistic research and translational validation.