Biology subjects

Dehestani, M.

Publications and source records attributed to Dehestani, M..

2 recordsLinked to original sources

bioRxiv2024

Single-cell transcriptomic changes in oligodendrocytes and precursors derived from Parkinson's disease patient-iPSCs with LRRK2-G2019S mutation

Despite extensive research, the contribution of the LRRK2 p.G2019S mutation to Parkinsons disease (PD) remains unclear. Recent findings indicate oligodendrocytes (ODCs) and their progenitors are vulnerable in PD pathogenesis. Notably, oligodendrocyte precursor cells (OPCs) exhibit high endogenous expression of LRRK2. We induced PD patient-iPSCs with the LRRK2 p.G2019S mutation into oligodendroglial lineages and performed single-cell RNA sequencing. Cell type composition analysis revealed an increase in 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 down-regulation of genes related to myelin assembly in ODCs, semaphorin-plexin pathway in OPCs, and cilium movement in proliferating OPCs. Cell-cell communication analysis identified significant alterations in several signaling pathways including a deactivation of PSAP signaling and an activation of MIF signaling in LRRK2 lines. Additionally, we observed an overall increase in SEMA6 signaling communication in LRRK2 cell lines; however, OPCs derived from these LRRK2 lines specifically lost SEMA6 signaling due to a down-regulation of SEMA6A and PLXNA2. Pseudotemporal trajectory analysis revealed that SHH had significantly altered expression along the pseudotime, accompanied by higher expression levels in LRRK2 lines. We propose that dysfunctional semaphorin-plexin signaling, along with cilia movement and SHH signaling, might represent early events in PD pathology.

neuroscience↗

bioRxiv2023

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 Parkinsons 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.

neuroscience↗