Systematic characterization of LUHMES cell-based Parkinson's disease models reveals potential novel drug targets.

Parkinson's disease (PD) encompasses incurable and progressive loss of dopaminergic neurons in patients and the research for effective disease-modifying treatments are still ongoing. In this study, using a systems biology-based approach we show that 6-OHDA treatment of alpha-synuclein-overexpressing LUHMES cells can be used as a physiologically relevant model of PD. RNAseq analysis in these LUHMES-based disease models validate genes including HMOX1 and IGF2R in common with previously identified PD genes. We further confirm that quercetin and rutin can partially alleviate cell death in this model and show that the expression of genes related to PD as well as those related to mitochondria and energy metabolism are back to basal levels in control cells upon quercetin or rutin pre-treatment. When RNAseq analysis was performed on drug-pretreated LUHMES PD models, protein folding, misfolded protein binding and unfolded protein response pathways were found to be affected. We believe these findings offer new avenues of innovative therapeutic strategies for PD. Overall design: Differentiated wildtype LUHMES cells or cells overexpressing alpha-synuclein were treated with 6-OHDA to generate the in vitro PD models. RNA-seq analysis was performed for four samples in each group. Quercetin (CEBPB) or rutin (AKR13C) were applied to 6-OHDA treated alpha-synuclein overexpressing LUHMES cells to test their neuroprotective effect.