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  • Book
    Blake Byers.
    Studies of Parkinson's disease (PD) have been greatly hindered by lack of access to affected human dopaminergic (DA) neurons. Here, we report generation of induced pluripotent stem cells that carry the p.G2019S mutation (LRRK2-G2019S-iPSCs) in the Leucine-Rich Repeat Kinase-2 (LRRK2) gene, the most common PD-related mutation; pluripotent lines that cells that carry a full SNCA gene triplication on one allele; and control pluripotent lines. We demonstrate that these PD autosomal dominant mutant LRRK2-G2019S-iPSCs, SNCA-triplication-iPSCs and Control-iPSCs were able to differentiate into dopaminergic neurons and showed increased expression of key oxidative stress response genes and alpha-synuclein protein. Moreover, LRRK2-G2019S iPSC derived dopaminergic neurons, specifically, were more sensitive to caspase-3 activation caused by exposure to hydrogen peroxide, MG-132, and 6-hydroxydopamine, compared to control dopaminergic neurons. While, SNCA-triplication iPSC derived dopaminergic neurons formed early ubiquitin positive puncta and were more sensitive to peak toxicity hydrogen peroxide induced cell stress. These findings suggest that LRRK2-G2019S and SNCA-triplication iPSC derived dopaminergic neurons exhibit early phenotypes linked to PD. Due to the high penetrance of the LRRK2 mutation, the expression of wild type protein in the SNCA-triplication line, and the clinical resemblance of patients afflicted with these disorders to sporadic PD patients, these neurons may provide a valuable platform for identification of novel pharmacological agents and diagnostics for modeling and alleviation of a subset of disease phenotypes.