Single-cell RNA profiling of oligodendroglial lineage cells derived from iPSCs carrying Parkinson's disease-relevant LRRK2-G2019S mutation.

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Recent findings indicate oligodendrocytes (ODCs) and their progenitors are vulnerable in Parkinson's disease (PD) pathogenesis. Notably, oligodendrocyte precursor cells (OPCs) exhibit high endogenous expression of the PD-relevant gene LRRK2. We differentiated iPSCs carrying the PD-relevant LRRK2 p.G2019S mutation into oligodendroglial lineages and performed single-cell RNA sequencing. Cell-type composition analysis revealed an increased proportion of OPCs, proliferating OPCs, and ciliated ependymal cells in LRRK2 lines, all of which are characterized by LRRK2 expression. Differential expression analysis revealed transcriptomic changes in several pathways, including downregulation of genes related to myelin assembly in ODCs, semaphorin-plexin pathway in OPCs, and cilium movement in proliferating OPCs. Pseudotemporal trajectory analysis revealed that SHH had significantly altered expression along the pseudotime, accompanied by higher expression levels in LRRK2 lines. We provide a single-cell transcriptomic atlas of iPSC-derived oligodendroglial lineage cells carrying the PD-relevant LRRK2 p.G2019S mutation and control lines.

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