RESUMO
Common disorders, including diabetes and Parkinson's disease, are caused by a combination of environmental factors and genetic susceptibility. However, defining the mechanisms underlying gene-environment interactions has been challenging due to the lack of a suitable experimental platform. Using pancreatic ß-like cells derived from human pluripotent stem cells (hPSCs), we discovered that a commonly used pesticide, propargite, induces pancreatic ß-cell death, a pathological hallmark of diabetes. Screening a panel of diverse hPSC-derived cell types we extended this observation to a similar susceptibility in midbrain dopamine neurons, a cell type affected in Parkinson's disease. We assessed gene-environment interactions using isogenic hPSC lines for genetic variants associated with diabetes and Parkinson's disease. We found GSTT1-/- pancreatic ß-like cells and dopamine neurons were both hypersensitive to propargite-induced cell death. Our study identifies an environmental chemical that contributes to human ß-cell and dopamine neuron loss and validates a novel hPSC-based platform for determining gene-environment interactions.
Assuntos
Cicloexanos/toxicidade , Diabetes Mellitus/induzido quimicamente , Neurônios Dopaminérgicos/efeitos dos fármacos , Interação Gene-Ambiente , Células Secretoras de Insulina/efeitos dos fármacos , Praguicidas/toxicidade , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Diferenciação Celular , Diabetes Mellitus/genética , Diabetes Mellitus/patologia , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/enzimologia , Glutationa Transferase/deficiência , Glutationa Transferase/genética , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/enzimologia , Mesencéfalo/citologia , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/enzimologia , Camundongos , Modelos Biológicos , Doença de Parkinson/etiologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/enzimologiaRESUMO
Genome-wide association studies (GWASs) have increased our knowledge of loci associated with a range of human diseases. However, applying such findings to elucidate pathophysiology and promote drug discovery remains challenging. Here, we created isogenic human ESCs (hESCs) with mutations in GWAS-identified susceptibility genes for type 2 diabetes. In pancreatic beta-like cells differentiated from these lines, we found that mutations in CDKAL1, KCNQ1, and KCNJ11 led to impaired glucose secretion in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1 mutant insulin+ cells were also hypersensitive to glucolipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-specific defects in vitro and in vivo by inhibiting the FOS/JUN pathway. Our approach of a proof-of-principle platform, which uses isogenic hESCs for functional evaluation of GWAS-identified loci and identification of a drug candidate that rescues gene-specific defects, paves the way for precision therapy of metabolic diseases.