A human striatal-midbrain assembloid model of alpha-synuclein propagation

초록

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 (hPSC)-derived neural organoids have provided improved access to study PD aetiology. This study established a method to generate human striatal-midbrain assembloids (hSMAs) from hPSCs for modelling alpha-synuclein (alpha-syn) propagation and recapitulating basal ganglia circuits, including nigrostriatal and striatonigral pathways.Human striatal organoids and midbrain organoids were generated using a stepwise differentiation protocol from hPSCs, and both regionalized neural organoids were assembled to form hSMAs, mimicking some basal ganglia circuits. Both the nigrostriatal and striatonigral pathways were present, and the neurons, such as dopaminergic neurons and GABAergic neurons, were electrophysiologically active in the hSMAs. Development of hSMAs in the presence of increased alpha-syn from SNCA overexpression induced nigrostriatal system damage, which is typical of the disease. Using the alpha-syn-linker-mKO2 reporter and a bimolecular fluorescence complementation system, we demonstrated that fluorescent alpha-syn was retrogradely transported from the striatal area to dopaminergic neurons of the midbrain area and exhibited alpha-syn aggregates and Lewy body-like inclusions. Furthermore, phosphorylated and detergent-resistant alpha-syn aggregates, similar to the pathological form in human patients, accumulated in the midbrain area of hSMAs. Treatment with a protein aggregation inhibitor (Anle138b) and an autophagy inducer (rapamycin) reduced alpha-syn aggregation, indicating the potential of hSMAs for drug testing.This study established hSMAs as a novel platform for modelling PD, demonstrating alpha-syn propagation and associated neural pathologies. These assembloids offer significant potential for developing therapeutic strategies and understanding the mechanisms of PD progression.,Tran et al. have developed a human striatal-midbrain assembloid model to study Parkinson's disease. The model recapitulates key disease features, including dopaminergic projection loss, alpha-synuclein propagation, and Lewy body pathology, supporting its utility for investigating disease mechanisms and testing potential treatments.,

키워드