Single-nucleus RNA-sequencing reveals oligodendrocytes and their progenitors as vulnerable cell types in prefrontal cortex and anterior cingulate of brains with Parkinson's disease.

Several prior studies have proposed the involvement of various brain regions and cell types in Parkinson's disease (PD) pathology. Here, we performed snRNA-seq on the prefrontal cortex and anterior cingulate regions from post-mortem control and PD brain tissue. We found a significant association of oligodendrocytes and oligodendrocyte precursor cells with PD-linked risk loci and report several dysregulated genes and pathways, including regulation of tau-protein kinase activity, regulation of inclusion body assembly and protein processing involved in protein targeting to mitochondria. In an independent PD cohort with clinical measures (681 cases and 549 controls), polygenic risk scores derived from the dysregulated genes significantly predicted Montreal Cognitive Assessment (MoCA)-, and Beck Depression Inventory-II (BDI-II)-scores as well as Age at Onset but not motor impairment (UPDRS-III). These results suggest that by expanding our focus to glial cells, we can uncover molecular pathways associated with non-motor symptoms that are frequently observed in PD patients, also prior to diagnosis.