In this project we are aiming at generating prototype midbrain organoids that are ready for distribution and various applications. Before being able to generate these prototypes we first need to standardize their production. Additionally, we will provide a proof-of-concept for the application in toxicology testing and neurodegeneration.The risk to suffer from Parkinson’s disease clearly increases with exposure to pesticides. Pesticides, herbicides, and fungicides are potent toxicants that may cause a degeneration of dopaminergic neurons which leads to Parkinson’s disease. Interestingly, even ambient exposure to pesticides has been described to strongly increase the risk of Parkinson’s disease. Furthermore, even extremely low-level pesticide exposure seem to be sufficient to cause Parkinson’s disease. A recent study revealed for 11 pesticides that they increase the risk for Parkinson’s disease. Also in this study very low level exposure was already toxic. This raises the question why this kind of toxicity was not detected earlier, which should have led to a stop of usage for these pesticides. We hypothesize that with more advanced models like the one that we are presenting in this proposal, the toxic potential of these pesticides could have been identified.Besides the usage as a toxicity model our project will also address the need for a physiologically more relevant model to test neuroprotective drugs (with a specific focus on Parkinson’s disease). There is a very clear need for such a model because the established in vivo animal tests as well as standard cell culture models do not sufficiently resemble the natural physiology of human dopaminergic neurons. The current technologies available to screen drug candidates against central nervous system diseases are inadequate, they do not recapitulate the physiology to a sufficient degree and therefore generate high failure rates. In this period of new opportunities, we have developed an organoid model recapitulating the key features of the region of the brain primarily affected by Parkinson’s disease, the midbrain. Our project addresses the huge unmet need of developing human-specific in vitro models which recapitulate the main features of the midbrain. We offer a human-derived tissue where toxin induced neurodegeneration can be detected, disease-mechanisms can be studied and promising therapeutic candidates can be screened.