Tsitkov, S. | Search bioRxiv

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

Disease related changes in ATAC-Seq of more than 450 iPSC-derived motor neuron lines from ALS patients and controls

Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured by ATAC-seq, of motor neuron cultures derived from a diverse group of 380 ALS patients and 80 healthy controls. We find that chromatin accessibility is heavily influenced by sex, the iPSC cell type of origin, ancestry, and the inherent variance arising from sequencing. Once these covariates are corrected for, we are able to identify robust ALS-specific signals in the data. Additionally, we find that the ATAC-seq data is able to predict ALS disease progression rates with similar accuracy to methods based on biomarkers and clinical status. These results suggest that iPSC-derived motor neurons recapitulate important disease-relevant epigenomic changes.

neuroscience↗