iPSC-Derived Dopamine Neurons Reveal Differences between Monozygotic Twins Discordant for Parkinson’s Disease

• DOI: 10.1016/j.celrep.2014.10.023
• Publication Date: 2014-11-06T18:50:38Z
• Authors: Chris M. Woodard; Brian A. Campos; Sheng-Han Kuo; Melissa J. Nirenberg; Michael W. Nestor; Matthew Zimmer; Eugene V. Mosharov; David Sulzer; Hongyan Zhou; Daniel Paull; Lorraine Clark; Eric E. Schadt; Sergio Pablo Sardi; Lee Rubin; Kevin Eggan; Mathew Brock; Scott Lipnick; Mahendra Rao; Stephen Chang; Aiqun Li; Scott A. Noggle
• Keywords: Male; 0301 basic medicine; Monoamine Oxidase Inhibitors; QH301-705.5; Sequence Analysis, RNA; Dopamine; Dopaminergic Neurons; Cell Membrane; Induced Pluripotent Stem Cells; Parkinson Disease; Twins, Monozygotic; Flow Cytometry; 03 medical and health sciences; Phenotype; Mutation; alpha-Synuclein; Glucosylceramidase; Humans; Biology (General); Monoamine Oxidase; Biomarkers

Parkinson's disease (PD) has been attributed to a combination of genetic and nongenetic factors. We studied a set of monozygotic twins harboring the heterozygous glucocerebrosidase mutation (GBA N370S) but clinically discordant for PD. We applied induced pluripotent stem cell (iPSC) technology for PD disease modeling using the twins' fibroblasts to evaluate and dissect the genetic and nongenetic contributions. Utilizing fluorescence-activated cell sorting, we obtained a homogenous population of "footprint-free" iPSC-derived midbrain dopaminergic (mDA) neurons. The mDA neurons from both twins had ∼50% GBA enzymatic activity, ∼3-fold elevated α-synuclein protein levels, and a reduced capacity to synthesize and release dopamine. Interestingly, the affected twin's neurons showed an even lower dopamine level, increased monoamine oxidase B (MAO-B) expression, and impaired intrinsic network activity. Overexpression of wild-type GBA and treatment with MAO-B inhibitors normalized α-synuclein and dopamine levels, suggesting a combination therapy for the affected twin.