Parkinson’s disease in a dish: The emerging role of organoids in research and therapy

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic (DA) neurons in the substantia nigra and the accumulation of α-synuclein aggregates, leading to motor and non-motor dysfunctions. The pathogenesis of PD involves a complex interplay of genetic mutations, environmental factors, and cellular mechanisms, including mitochondrial dysfunction, impaired proteostasis, neuroinflammation, and gut-brain axis dysregulation. Traditional research models, such as animal models and two-dimensional cell cultures, have provided valuable insights but often fall short in replicating the multifaceted and progressive nature of PD, especially in sporadic cases. The emergence of organoid technology offers a transformative approach to PD research. This technology enables the generation of three-dimensional structures that closely mimic the architecture, cellular composition, and functionality of the human midbrain. Midbrain organoids have become pivotal models for investigating disease mechanisms, including DA neuron degeneration, α-synuclein aggregation, and neuroinflammatory responses. Moreover, organoids enable high-throughput drug screening and the identification of potential therapeutic targets. Beyond modeling, recent advancements have demonstrated the feasibility of organoid transplantation as a therapeutic strategy. This review summarizes the current progression of organoid technology in PD research, focusing on its application in modeling pathomechanisms, drug discovery, and therapeutic applications. Despite being in its early stages, organoid technology holds significant promise for advancing our understanding of PD pathogenesis and developing translational therapies.