Integrated Label Transfer for Oligodendrocyte Subpopulation Profiling in Parkinson's Disease and Multiple System Atrophy

Abstract

Transfer of cell type labels as part of the comprehensive integration of multiple single nucleus RNA sequencing (snRNAseq) datasets offers a powerful tool for comparing cell populations and their activation states in normal versus disease conditions. Another potential use for these methods is annotation alignments between samples from different anatomic areas. This study describes and evaluates an integration analysis applied for profiling of oligodendrocyte lineage nuclei sequenced from human brain putamen region tissue samples for healthy Control (n = 3), Parkinson’s Disease (PD; n = 3) and Multiple System Atrophy (MSA; n = 3) subjects with label transfer to substantia nigra region tissue samples for healthy Control (n = 5) subjects. PD and MSA are both synucleinopathies, progressive neurodegenerative disorders characterized by nervous system aggregates of α-synuclein, a protein encoded by the SNCA gene. Histologic findings and genetic evidence suggest links between oligodendrocyte biology and synucleinopathy pathogenesis. In this work, we first identify disease-associated changes among transcriptionally distinct oligodendrocyte subpopulations in putamen. We then apply label transfer methods to generalize our findings from putamen to substantia nigra, a brain region characteristically impacted in PD and variably affected in MSA. Interestingly, our analysis predicts oligodendrocytes in substantia nigra include a significantly greater proportion of an oligodendrocyte subpopulation identified in putamen as most highly overexpressing SNCA in PD. Our results provide new insights into oligodendrocyte biology in PD and MSA and our workflow provides an example of label transfer methods applied for cross-dataset exploratory purpose.