1. iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson's disease.
- Author
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Woodard CM, Campos BA, Kuo SH, Nirenberg MJ, Nestor MW, Zimmer M, Mosharov EV, Sulzer D, Zhou H, Paull D, Clark L, Schadt EE, Sardi SP, Rubin L, Eggan K, Brock M, Lipnick S, Rao M, Chang S, Li A, and Noggle SA
- Subjects
- Biomarkers metabolism, Cell Membrane drug effects, Cell Membrane metabolism, Dopamine metabolism, Dopaminergic Neurons drug effects, Dopaminergic Neurons enzymology, Flow Cytometry, Glucosylceramidase genetics, Humans, Induced Pluripotent Stem Cells drug effects, Male, Monoamine Oxidase metabolism, Monoamine Oxidase Inhibitors pharmacology, Mutation genetics, Parkinson Disease enzymology, Phenotype, Sequence Analysis, RNA, alpha-Synuclein metabolism, Dopaminergic Neurons pathology, Induced Pluripotent Stem Cells pathology, Parkinson Disease pathology, Twins, Monozygotic
- Abstract
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., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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