Objective: To explore the spatial organization and cellular complexity of the orbitofrontal cortex (OFC) in multiple system atrophy (MSA) via spatial transcriptomic (SRT).

Background: The OFC is the most regional contributor to the advanced gray matter aging in MSA versus controls (Ctrl) [1]. However, the cellular and functional heterogeneities in OFC have not been elucidated.

Method: Two human postmortem frozen brains from the OFC of 1 MSA and 1 Ctrl were cryosectioned. The 10X Genomics Visium platform was utilized. Data were processed by Seurat. Clusters were generated by the shared nearest neighbor modularity optimization. Cell-type annotation and pathway enrichment analysis were conducted using AUCell on the gene sets from MSigDB.

Results: After quality control and integration, an expression matrix containing 8,030 spots and 15,387 features was obtained. Among 9 clusters identified, neurons (Cluster(C) 1-3, & 9), astrocyte (C4), oligodendrocyte (oligo) (C5), interneurons (C6-7), and endothelial cells (C8) were labeled by cell type markers. Interestingly, microglia markers (CD74, CSF1R, SPP1) were only enriched within C5 expressing oligo markers (MBP, MOBP, PLP1, CNP). Inflammation, lipid metabolism, neurogenesis, and SNCA-related pathways were significantly altered in all clusters. In contrast, the apoptosis-related pathway was altered majorly in astrocytes (C4); the heme metabolism-related pathway was altered in oligo (C5). Among differentially expressed genes (P ≤ 0.05 & fold change ≥ 1.25), SNCA was up-regulated in C1, C3, C4, C5, C8-9, and down-regulated in a subpopulation of sensory neurons (C2) of MSA. A school of myelin-related genes (MOG, MOBP, PLP1, CNP) was upregulated in oligo (C5) of MSA.

Conclusion: The results of SRT are aligned with previous studies, echoing the roles of excessive neuroinflammation, lipid dysmetabolism, and aberrant neurogenesis in MSA. We also uncover complex cellular and genetic heterogeneities in OFC of MSA, including 1) extensive SNCA overexpression in all cell populations while downregulated in a subtype of sensory neurons, 2) upregulated myelin-related gene sets in pathologically demyelinated oligo, and 3) exclusive enrichment of microglia with oligo. The weaving mechanisms of synucleinopathy, oligodendropathy, and microglia-mediated neuroinflammation in MSA await further studies.

References: [1] Chen CL, Kuo MC, Wu WC, Hsu YC, Wu RM, Tseng WI. Advanced brain aging in multiple system atrophy compared to Parkinson’s disease. Neuroimage Clin. 2022;34:102997.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/explore-cellular-heterogeneities-of-orbitofrontal-cortex-in-multiple-system-atrophy-using-spatial-transcriptomics/