Assay of chemicals for Parkinson's toxicity in human iPSC-derived neurons

Parkinson s DiseasePDafflictsof humans and prevalence increases with ageInitial symptoms include tremors in extremitiesbut PD progresses over yearsaffecting additional limbswith impairment of mood behavior cognitionFamilial PD makes upof cases while certain chemicals environmental toxicantse grotenoneparaquatmanebincrease the risk of PD and much evidence points to genetic x environmental interactionsThe overall goal of our project is to develop an assay systemutilizing dopaminergic neurons derived from induced pluripotent stem cellsiPSC DNs and iPSC MGsand automated digital microscopy and associated methodsKinetic Image CytometryKICand High Content AnalysisHCAto enable screening of environmental toxicants for potential PD toxicityIn phase I we demonstrated that iPSC DN featuring the ATSyn mutationwhich causes early onset PDwith high penetrancehave increased spontaneous activitycalcium and voltage transientsand increased sensitivity to PD linked toxicants vsneurons with wtSynwhich demonstrates the feasibility of our approachIn Phase II we will collaborate with researchers at The Parkinson s Institute and Clinical Centerto further develop our assay methodsutilizing iPSC DNs that feature GS LRRKa commonPD associated mutationthat has very recently been linked to increased susceptibility to environmental toxicantsiPSC lines representing both sexesand lines derived from subjects with sporadic PDWe will also develop a coculture system with both iPSC DNs and iPSC MGs in the culture wellsThe resulting assay system will enable the most comprehensive screening of environmental toxicants for potential PD inducing effectsyet availablePotential customers for the assay include government agenciessuch as the US EPA and the National Toxicology Programand global agencies concerned with the effects of industrial agricultural chemicals on human health Parkinson s DiseasePDafflictsof humansparticularly the elderlyInitial symptoms include tremors which worsenpatients also commonly develop depression and dementiaand there is currently no curePD occurs because neurons die in the region of the brain that controls movementWhile PD runs in certain familiescertain gene mutations increase risk of PDmost cases occur without a family history of the diseasethis was a mystery until it was realized that certain chemicalsparticularly agricultural pesticides and industrial solvents can trigger PDEach year thousands of new chemicals are developed and used for industrial agricultural purposes but there is currently no way to predict if these new chemicals will cause PDOur project will develop a test system to identify chemicals that cause PDThe test system will use neurons derived from stem cellsthe type of stem cells comes from skin cellsobtained from painless skin biopsiesnot embryosThe chemicals will be applied to the stem cell derived neurons to see if they have harmful effectsSteps can then be taken to limit exposure to PD causing chemicalsthereby improving human health