A deeper understanding of early disease mechanisms occurring in Parkinson’s disease (PD) is needed to reveal restorative targets. Here we report that human induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) obtained from healthy individuals or patients harboring LRRK2 PD-causing mutation can create highly complex networks with evident signs of functional maturation over time. Compared to control neuronal networks, LRRK2 PD patients’ networks displayed an elevated bursting behavior, in the absence of neurodegeneration. By combining functional calcium imaging, biophysical modeling, and DAn-lineage tracing, we found a decrease in DAn neurite density that triggered overall functional alterations in PD neuronal networks. Our data implicate early dysfunction as a prime focus that may contribute to the initiation of downstream degenerative pathways preceding DAn loss in PD, highlighting a potential window of opportunity for pre-symptomatic assessment of chronic degenerative diseases.

需要更深入地了解帕金森病 (PD) 中发生的早期疾病机制，以揭示修复目标。在这里我们报告说，从健康个体或携带 LRRK2 PD 突变的患者中获得的人类诱导多能干细胞 (iPSC) 衍生的多巴胺能神经元 (DAn) 可以创建高度复杂的网络，随着时间的推移具有明显的功能成熟迹象。与对照神经元网络相比，LRRK2 PD 患者的网络在没有神经变性的情况下表现出更高的爆发行为。通过结合功能性钙成像、生物物理建模和 DAn 谱系追踪，我们发现 DAn 神经突密度的降低引发了 PD 神经元网络的整体功能改变。