Dissecting the transcriptome of Parkin (PRKN)-linked Parkinson’s disease using 2D and 3D hiPSC-neuronal models

Parkin is an E3 ubiquitin ligase, involved in protein quality control and the removal of damaged mitochondria. Here, we generate human induced pluripotent stem cell (hiPSC)-derived midbrain dopaminergic neurons using both a 2D differentiation protocol and our recently developed 3D method based on the microencapsulation of hiPSCs in small alginate/fibronectin beads.

The transcriptional signature of cells from PD patients carrying PRKN mutations is evaluated at the neuronal stage and during the differentiation process. Analyses of mutation-specific gene sets and associated pathways reveal multiple biological processes implicated in PRKN-pathology, including synaptic and metabolic function, inflammation, and intracellular trafficking, reflecting a layered disease development. These data map the contribution of Parkin in early PD pathogenesis and progression before overt neurodegeneration.