Single Nuclei Sequencing of Human Putamen Oligodendrocytes Reveals Altered Heterogeneity and Disease-Associated Changes in Parkinson’s Disease and Multiple System Atrophy

Abstract The role of oligodendrocytes in neurodegenerative diseases remains incompletely understood and largely unexplored at the single cell level. We profiled 87,086 single nuclei from human brain putamen region for healthy control, Parkinson’s Disease (PD), and Multiple System Atrophy (MSA). Oligodendrocyte lineage cells were the dominant cell-type in the putamen with oligodendrocyte subpopulations clustered by transcriptomic variation found to exhibit diverse functional enrichment patterns, and this oligodendrocyte heterogeneity was altered in a disease-specific way. Among profiled oligodendrocyte subpopulations, differences in expression of SNCA, HAPLN2, MAPT, APP, and OPALIN were observed for PD and MSA compared with healthy controls. Intriguingly, greater activation of unfolded protein response pathway gene expression was observed in PD nuclei versus MSA. Using network analysis, we then identified specific PD- and MSA-correlated gene co-expression modules enriched with disease relevant pathways; the PD-correlated module was significantly enriched for Parkinson’s Disease GWAS loci (p = 0.01046). Our analysis provides a broader understanding of oligodendrocyte heterogeneity and reveals distinctive oligodendrocyte pathological alterations associated with PD and MSA which may suggest potential novel therapeutic targets and new strategies for disease modification.