Insulin resistance disrupts midbrain metabolic and functional homeostasis and aggravates dopaminergic neuron loss in GBA-PD via FOXO1 overexpression [WTvsGBA]

Growing evidence indicates that Type 2 diabetes (T2D) is associated with an increased risk of developing PD Parkinson’s disease (PD) through shared disease mechanisms. Studies show that insulin resistance, which is the driving pathophysiological mechanism of T2D plays a major role in neurodegeneration by impairing neuronal functionality, metabolism, and survival. To better understand the importance of insulin signalling in the human midbrain, which is the most affected brain region in PD, we expose IPSC-derived human midbrain organoids from healthy individuals and GBA-N370S mutation-carrying PD patients to either high insulin concentrations, promoting insulin resistance, or to more physiological insulin concentrations restoring normal insulin signalling function. We are able to show that insulin resistance compromises dopaminergic neuron and dopamine levels in the midbrain organoids of healthy donors. Moreover, insulin-resistant organoids display diminished neuronal activity and reduced metabolic efficiency. Furthermore, our findings demonstrate FOXO1 role in GBA-PD phenotype severity and show the potential beneficial effects of the anti-diabetic drug Pioglitazone in GBA-PD treatment. Overall, our results highlight insulin resistance as a significant target in PD prevention and disease-modifying therapy.