Single-nuclei paired multiomic analysis of young, aged, and Parkinson’s disease human midbrain reveals age-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 of midbrain nuclei 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 age-associated oligodendrocyte subtype that appears during normal aging, characterized by elevated protein folding and chaperone-mediated autophagy pathways. Differential gene and protein-protein interaction analyses show that these functions are significantly compromised in PD. Peak-gene association from our paired data identifies differential cis-elements linked to regulation of differentially expressed genes between PD patients and neurologically healthy controls. Our study suggests a previously undescribed role for oligodendrocytes in aging and PD pathogenesis. Single-nuclei Multiome sequencing data were generated by deep sequencing *** Raw data for these human patients will be submitted for controlled access ***