This study investigated the disease mechanism of Parkinson's disease (PD) using midbrain dopaminergic (mDA) neurons differentiated from human induced pluripotent stem cells (hiPSCs) carrying the ILE368ASN mutation in the PINK1 gene. Single-cell RNA sequencing and gene expression analysis identified differentially expressed genes during mDA neuron differentiation. Network analysis revealed these genes form a core network interacting with all known Parkinson's disease-associated genes. This core network encompasses key PD-associated pathways. Proteomics analysis showed consistent alteration in proteins of dopamine metabolism, indicating a defect in dopaminergic metabolism. The findings suggest a converging network for PD-associated pathways, offering an inclusive interpretation of PD's phenotypic heterogeneity.

Gabriela Novak, Dimitrios Kyriakis, Kamil Grzyb, Michela Bernini, Sophie Rodius, Gunnar Dittmar, Steven Finkbeiner, Alexander Skupin