Distinctive genomic signature of neural and intestinal organoids from familial Parkinson's disease patient‐derived induced pluripotent stem cells

Aims The leucine‐rich repeat kinase 2 ( LRRK 2) G2019S mutation is the most common genetic cause of Parkinson's disease ( PD ). There is compelling evidence that PD is not only a brain disease but also a gastrointestinal disorder; nonetheless, its pathogenesis remains unclear. We aimed to develop human neural and intestinal tissue models of PD patients harbouring an LRRK 2 mutation to understand the link between LRRK 2 and PD pathology by investigating the gene expression signature. Methods We generated PD patient‐specific induced pluripotent stem cells ( iPSC s) carrying an LRRK 2 G2019S mutation ( LK 2 GS ) and then differentiated into three‐dimensional (3D) human neuroectodermal spheres ( hNES s) and human intestinal organoids ( hIO s). To unravel the gene and signalling networks associated with LK 2 GS , we analysed differentially expressed genes in the microarray data by functional clustering, gene ontology ( GO ) and pathway analyses. Results The expression profiles of LK 2 GS were distinct from those of wild‐type controls in hNES s and hIO s. The most represented GO biological process in hNES s and hIO s was synaptic transmission, specifically synaptic vesicle trafficking, some defects of which are known to be related to PD . The results were further validated in four independent PD ‐specific hNES s and hIO s by microarray and qRT ‐PCR analysis. Conclusion We provide the first evidence that LK 2 GS also causes significant changes in gene expression in the intestinal cells. These hNES and hIO models from the same genetic background of PD patients could be invaluable resources for understanding PD pathophysiology and for advancing the complexity of in vitro models with 3D expandable organoids.