Single-nuclei paired multiomic analysis of young, aged, and Parkinson’s disease human midbrain reveals age- and disease-associated glial changes and their contribution to Parkinson’s disease

Age is the primary risk factor for Parkinson’s disease (PD), but how aging changes the expression and regulatory landscape of the brain remains unclear. Here, we present a single-nuclei multiomic study profiling shared gene expression and chromatin accessibility of young, aged and PD post-mortem midbrain samples. Combined multiomic analysis along a pseudopathogenesis trajectory reveals all glial cell types are affected by age, but microglia and oligodendrocytes are further altered in PD. We present evidence for a novel disease-associated oligodendrocyte subtype and identify genes lost over the aging and disease process, including CARNS1, that may predispose healthy cells to develop a disease-associated phenotype. Peak-gene association analysis from paired data identifies 89 PD-associated SNP loci, including five in MAPT, that show differential association with gene expression in disease-associated oligodendrocytes. Our study suggests a previously undescribed role for oligodendrocytes in aging and PD pathogenesis.