Exploring Brain Disease Mechanisms Using an iPSC-derived Brain Organoid Model

The advent of stem cell-based 3D cell culture platforms marked the beginning of a new era for in vitro biomedical research. These microscopic organo-typic structures reproduce human organs in a dish with significantly higher accuracy than traditional monolayer cell culture models. Brain organoids have become a pivotal tool in the investigation of various brain disorders. This PhD thesis encompasses three distinct original studies and one narrative review, all dedicated to exploring the intricate pathophysiological mechanisms associated with both neurodevelopmental and neurodegenerative disorders. The findings contribute to the current body of knowledge, shedding light on critical aspects of these disorders and providing a foundation for further research in the field. In one study, we investigated how a mutation in a gene (CHD8) and exposure to an environmental factor (chlorpyrifos) could synergistically induce pathological alterations associated with autism spectrum disorder, using an innovative model of brain organoids. In another study, we have employed our brain organoid model to analyze the feasibility of inferring transcriptional changes in the brain through the analysis of mRNA levels in blood EV. Furthermore, we have studied medicinal mushrooms as nutritional supplements for potential treatments in neurodegenerative disorders. We have demonstrated the efficacy of the association of C. versicolor and H. erinaceus to prevent oxidative stress induced by rotenone by acting on the Nrf2/HO-1 pathway, and to resolve the neuroinflammatory processes associated to PD. Finally, we have suggested mechanisms through which these compounds could be beneficial in autistic patients.