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

Parkinson disease is increasingly recognized as a systemic disorder involving pathological communication along the brain-gut axis, yet the cellular mechanisms underlying inter-organ -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 -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 -synuclein propagation, with NRXN1 being upregulated in Parkinsons 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 -synuclein propagation in Parkinsons disease.