Multiscale Transcriptomic Network Models of Parkinson’s Disease at the Single Cell Level

Multiple single nuclei RNA-sequencing (snRNA-seq) studies of the vulnerable brain regions of Parkinson's Disease (PD) have revealed alterations in brain cell populations and cell type specific transcriptomes. However, a systematic analysis of cell-type-resolved gene regulatory architecture in PD is lacking. Here, we develop an integrative, meta-cell based multiscale network analysis (MCMNA) of snRNA-seq data from the substantia nigra to systematically uncover molecular mechanisms and identify potential therapeutic targets for PD. MCMNA overcomes the inherent sparsity of single cell data by leveraging metacell-based aggregation, enabling construction of robust gene regulatory networks. Gene co-expression network analysis identifies cell-type specific gene modules associated with PD. Integration of meta-cell based differential gene expression and a Bayesian causal network systematically reveals putative driver genes and their hierarchies. Our multiscale network models provide a framework for prioritizing candidate molecular regulators and pathways for further investigation of disease mechanisms and therapeutic targets.