MODELING GENETIC HETEROGENEITY IN PARKINSON’S DISEASE USING PATIENT-DERIVED DOPAMINERGIC NEURONS AND MULTI-OMICS APPROACHES

The genetic of Parkinson’s disease (PD) has been increasingly explored in recent years. Our studies demonstrated a polygenic model of inheritance involving multiple rare variants in novel PD-associated genes. Although rare variants are now recognized as major contributors to disease risk, their functional impact remains largely unexplored in human disease-relevant cellular systems.
In this study, we generated dopaminergic neurons by differentiating hiPSCs derived from PD patients carrying rare variants in novel PD genes. We investigated disease-associated molecular alterations by combining electrophysiological analyses with integrative multi-omics approach, including proteomic, lipidomic, and genetic analyses.
Electrophysiological characterization revealed altered cell capacitance and action potential properties among PD-derived neurons, indicating functional heterogeneity within the patient group. Multi-omics profiling revealed a dual molecular landscape. PD-derived neurons displayed convergent protein alterations, notably involving Calpastatin and CXCR4, suggesting novel contributors to PD pathophysiology. Pathway-level analyses uncovered distinct molecular signatures across PD patients. Neurons derived from PD1, PD4, and PD6 patients carrying variants in KIF21B, SLC6A3, HMOX2, TMEM175, and AIMP2 exhibited marked increases in fatty acids and sphingolipids. These alterations were accompanied by dysregulation of key enzymes involved in glycolysis (ENO2, ALDOA/C, PKM, PFKL), oxidative phosphorylation (CAT, UQCR10, COX7C), and mitochondrial dynamics and stability (OPA1, MFN1, LONP1).
Importantly, genetic association analyses supported these findings by identifying PD-associated variants in genes encoding enzymes belonging to the altered pathways.
Overall, our study demonstrates that integrating genetic analyses with multi-omics profiling of patient-derived hiPSC dopaminergic neurons captures shared and patient-specific aspects of PD biology and supports future precision medicine approaches.