Single cell transcriptomics of human PINK1 iPSC differentiation dynamics reveal a core network of Parkinson’s disease

Abstract Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons (mDA) in the midbrain. The heterogenous pathology and complex underlying mechanisms are only partly understood and there is no treatment able to reverse PD progression. Here, we targeted the disease mechanisms by focusing on the ILE368ASN mutation within the PINK1 (PARK6) gene and systematically characterized midbrain dopaminergic neurons obtained from human induced pluripotent stem cells (iPSCs). Single-cell RNA sequencing (RNAseq) and pairwise analysis of gene expression identified genes consistently differentially expressed during the mDA neuron differentiation process. Subsequent network analysis revealed that these genes form a core network, which interacts with all known 19 protein-coding Parkinson’s disease-associated genes and includes ubiquitination, mitochondrial, protein processing, RNA metabolism, and secretory pathways as important subnetworks. Our findings indicate a unified network underlying PD pathology and offers new interpretation of the phenotypic heterogeneity of PD.