Abstract: Parkinson’s disease (PD), the second most common neurodegenerative disorder, is a multifactorial disease involving interplay of genetics, aging, and environmental factors. Given that most drugs entering clinical trials fail to reach patients or effectively mitigate PD, there is an urgent need to explore novel therapeutic strategies using advanced patient-specific model systems. Very recent observatory studies revealed a correlation between glucagon-like peptide-1 (GLP-1) receptor agonists, commonly known as "anti-obesity medication", and the slowing of PD symptoms progression in both animal models and humans. These findings raised numerous questions about the cellular and metabolic mechanisms by which GLP-1 receptor agonists alleviate PD symptoms. To investigate this, we developed midbrain organoids derived from PD patients. By harnessing PD patient-specific induced pluripotent stem cells (iPSCs) from the unique PD mutations, LRRK2 and GBA1, we generate midbrain organoids that mimic the substantia nigra, the brain region most affected in PD. As an initial step, we observed that the brain organoids express alpha-synuclein (α-Syn) in vitro and exhibit differential survival of dopaminergic neurons, which are hallmarks of PD. We evaluated the effects of GLP-1 receptor agonists on key PD phenotypes, including dopaminergic neurons survival, and α-Syn accumulation. Moreover, we preformed transcriptomic and metabolic profiling to identify molecular alterations associated with GLP-1 receptor agonist treatment. We are currently analyzing the results to explore the effects on PD- and metabolic-related pathways. This research tackles a timely challenge by employing patient-specific iPSCs-derived midbrain organoids model to study PD and explore potential treatments. Our findings highlight the therapeutic potential of GLP-1 receptor agonists in modulating PD-related phenotypes.
