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Cell Rep DOI:10.1016/j.celrep.2014.10.023

iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson's disease.

Publication TypeJournal Article
Year of Publication2014
AuthorsWoodard, CM, Campos, BA, Kuo, S-H, Nirenberg, MJ, Nestor, MW, Zimmer, M, Mosharov, EV, Sulzer, D, Zhou, H, Paull, D, Clark, L, Schadt, EE, Sardi, SPablo, Rubin, L, Eggan, K, Brock, M, Lipnick, S, Rao, M, Chang, S, Li, A, Noggle, SA
JournalCell Rep
Date Published2014 Nov 20
Keywordsalpha-Synuclein, Biomarkers, Cell Membrane, Dopamine, Dopaminergic Neurons, Flow Cytometry, Glucosylceramidase, Humans, Induced Pluripotent Stem Cells, Male, Monoamine Oxidase, Monoamine Oxidase Inhibitors, Mutation, Parkinson Disease, Phenotype, Sequence Analysis, RNA, Twins, Monozygotic

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.


Alternate JournalCell Rep
PubMed ID25456120
PubMed Central IDPMC4255586
Grant ListU01 AG046170 / AG / NIA NIH HHS / United States
K08NS083738 / NS / NINDS NIH HHS / United States
RF1 AG042965 / AG / NIA NIH HHS / United States
K08 NS083738 / NS / NINDS NIH HHS / United States
R01NS075222 / NS / NINDS NIH HHS / United States
R01 NS075222 / NS / NINDS NIH HHS / United States
1RF1AG042965-02 / AG / NIA NIH HHS / United States
1U01AG046170-01 / AG / NIA NIH HHS / United States