Modeling the pathological brain-gut axis in Parkinson’s disease using human iPSC derived brain-intestinal assembloids

ABSTRACT Parkinson’ disease is increasingly recognized as a systemic disorder involving pathological communication along the brain–gut axis, yet the cellular mechanisms underlying inter-organ α-synuclein propagation remain poorly defined. Here, we establish a human induced pluripotent stem cell–derived brain–intestinal assembloid that integrates a developmentally specified medullary hindbrain organoid with an enteric neuron–enriched intestinal organoid. Using this model, we show the propagation of α-synuclein from brainstem neurons to enteric neurons. Ligand–receptor analysis combined with genetic perturbation identifies NRXN1–NLGN2 signaling as a key mediator of brain-to-gut α-synuclein propagation, with NRXN1 being upregulated in Parkinson’s disease patient datasets in vivo . Together, these findings establish a human stem cell–based platform for investigating brain–gut communication and uncover molecular mechanisms underlying α-synuclein propagation in Parkinson’s disease.