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

Cell Rep. 2014 Nov 20;9(4):1173-82. doi: 10.1016/j.celrep.2014.10.023. Epub 2014 Nov 6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Twin Study

MeSH terms

  • Biomarkers / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Dopamine / metabolism
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / enzymology
  • Dopaminergic Neurons / pathology*
  • Flow Cytometry
  • Glucosylceramidase / genetics
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / pathology*
  • Male
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / pharmacology
  • Mutation / genetics
  • Parkinson Disease / enzymology
  • Parkinson Disease / pathology*
  • Phenotype
  • Sequence Analysis, RNA
  • Twins, Monozygotic*
  • alpha-Synuclein / metabolism


  • Biomarkers
  • Monoamine Oxidase Inhibitors
  • alpha-Synuclein
  • Monoamine Oxidase
  • Glucosylceramidase
  • Dopamine

Associated data

  • GEO/GSE62642