Distinctive genomic signature of neural and intestinal organoids from familial Parkinson's disease patient‐derived induced pluripotent stem cells
Interestingly, genome‐wide association studies (GWAS) have shown that LRRK2 mutations are also linked to intestinal inflammatory disorder, Crohn's disease and ulcerative colitis 17. Intestinal symptoms occasionally precede the classical PD motor symptoms by several years 18. In recent reports, patients with early PD have been documented to have increased intestinal epithelial permeability, bacterial invasion and high concentrations of inflammatory cytokines in colonic biopsies 19. Gastrointestinal involvement is common over the course of PD. Damage to the enteric nervous system (ENS) occurs during the early stage of PD, and the accumulation of pathological α‐synuclein in Lewy bodies in the ENS may lead to intestinal dysfunction in PD 21. A post mortem study showed the presence of Lewy bodies and neurites in the ENS in all cases that were examined pathologically 24. However, the molecular and cellular links between PD‐related mutations, such as G2019S substitution and intestinal dysfunction, remain elusive.
LRRK2 mutation‐associated variations in morphology, physiology and function have been related to discrepancies in the gene expression profiles of affected cells 26. There is reportedly a broad toxic effect of the G2019S mutation primarily in the neuronal context 27. Several gene expression profile studies of the G2019S mutation have been performed in post mortem PD brains, peripheral blood mononuclear cells (PBMCs) from PD patients and transgenic mouse models and cellular models of PD 7. Hence, the study of gene expression profiles related to the LRRK2 mutation in other cell types/tissues could provide clues to the causal gene networks and pathogenesis of PD. To address this issue, we tested the hypothesis that LRRK2 mutations could influence the expression of certain genes involved in various cell signalling processes underlying the pathophysiology of PD in both neural and intestinal tissues.
The fact that PD involves a widespread neurodegenerative process and many PD patients will also eventually develop gastrointestinal disorders led us to take advantage of induced pluripotent stem cell (iPSC) technology and the capacity of these cells to differentiate towards various cell types. Recently, neurons derived from PD‐specific iPSCs harbouring an LRRK2 G2019S (LK2GS) mutation have recapitulated the pathological features of PD, such as mitochondrial deficits with shorter mitochondria and reduced basal oxygen consumption rates 31, the accumulation of α‐synuclein, greater sensitivity to caspase‐3 activation and cell death 32.
We report here on PD‐relevant human tissue models in which three‐dimensional (3D) human neuroectodermal spheres (hNESs) and human intestinal organoids (hIOs) were obtained from PD patient‐specific iPSCs harbouring the LK2GS mutation. We performed an integrative and comparative analysis of the transcriptome profiles of hNESs and hIOs that carried the LK2GS mutation and wild‐type controls.