Generation of Human Striatal-Midbrain Assembloids From Human Pluripotent Stem Cells to Model Alpha-Synuclein Propagation

Animal models of the pathology of Parkinson’s disease (PD) have provided most of the treatments to date, but the disease is restricted to human patients. In vitro models using human pluripotent stem cell-derived neural organoids have provided improved access to study PD etiology. Here, we generated human striatal and midbrain organoids and assembled both regionalized neural organoids to form human striatal-midbrain assembloids (hSMAs), mimicking a part of basal ganglia. Both the nigrostriatal and striatonigral pathways are present and electrophysiologically active in the hSMAs. hSMA development in the presence of increased alpha-synuclein (α-syn) from SNCA overexpression, induced nigrostriatal system damage, which is typical of the disease. Using the α-syn-mKO2 reporter and bimolecular fluorescence complementation system, we demonstrated that fluorescent α-syn is transported from the striatal area tothe dopaminergic (DA) neurons of the midbrain area. Furthermore, insoluble α-syn aggregated over time in DA neurons similar to Lewy bodies in human patients. Such assembloids are a compelling new platform to develop novel PD therapeutic strategies.