Transcriptomic changes in oligodendrocytes and precursor cells predicts clinical outcomes of 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 (ODCs) and oligodendrocyte precursor cells (OPCs) 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 but not motor impairment (UPDRS-III). We extended our analysis of clinical outcome prediction by incorporating three separate datasets that were previously published by different laboratories. In the first dataset from the anterior cingulate cortex, we identified a correlation between ODCs and BDI-II. In the second dataset obtained from the substantia nigra (SN), OPCs displayed notable predictive ability for UPDRS-III. In the third dataset from the SN region, a distinct subtype of OPCs, labeled OPC_ADM, exhibited predictive ability for UPDRS-III. Intriguingly, the OPC_ADM cluster also demonstrated a significant increase in PD samples. These results suggest that by expanding our focus to glial cells, we can uncover region-specific molecular pathways associated with PD symptoms. Overall design: The study investigated postmortem brain tissues from four male Parkinson's disease (PD) patients and two healthy controls, aged between 65 and 80. The PD patients had either the LRRK2 G2019S or the GBA1 mutations (samples 1 and2 with L444P and samples 5 and 6 with E326K), while the controls were healthy. Brain regions, specifically the prefrontal cortex and anterior cingulate cortex, were analyzed. The tissues were sourced from the Netherlands Brain Bank and UCL Queen Square Brain Bank, adhering to institutional ethical guidelines. Single nuclei were isolated from the tissues using a detergent lysis technique, followed by RNA sequencing using 10x Genomics technology to generate single-cell gene expression libraries. Quality control and differential gene expression analyses were performed to identify disease-relevant cell types. The study also incorporated cell-type-specific gene expression association with genetic risk of PD using MAGMA and polygenic risk scores, highlighting differences in gene expression profiles between PD patients and controls.