Molecular Features Underlying Neurodegeneration Identified through In Vitro Modeling of Genetically Diverse Parkinson's Disease Patients

Cell Rep. 2016 Jun 14;15(11):2411-26. doi: 10.1016/j.celrep.2016.05.022. Epub 2016 Jun 2.


The fact that Parkinson's disease (PD) can arise from numerous genetic mutations suggests a unifying molecular pathology underlying the various genetic backgrounds. To address this hypothesis, we took an integrated approach utilizing in vitro disease modeling and comprehensive transcriptome profiling to advance our understanding of PD progression and the concordant downstream signaling pathways across divergent genetic predispositions. To model PD in vitro, we generated neurons harboring disease-causing mutations from patient-specific, induced pluripotent stem cells (iPSCs). We observed signs of degeneration in midbrain dopaminergic neurons, reflecting the cardinal feature of PD. Gene expression signatures of PD neurons provided molecular insights into disease phenotypes observed in vitro, including oxidative stress vulnerability and altered neuronal activity. Notably, PD neurons show that elevated RBFOX1, a gene previously linked to neurodevelopmental diseases, underlies a pattern of alternative RNA-processing associated with PD-specific phenotypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Cell Differentiation / drug effects
  • Cell Line
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Genes, Mitochondrial
  • Genetic Heterogeneity*
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism
  • Mesencephalon / pathology
  • Models, Biological
  • Nerve Degeneration / genetics*
  • Nerve Degeneration / pathology
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Neurites / drug effects
  • Neurites / metabolism
  • Neurotoxins / toxicity
  • Oxidative Stress / drug effects
  • Parkinson Disease / genetics*
  • Parkinson Disease / pathology
  • Phenotype
  • RNA Splicing Factors / genetics
  • RNA Splicing Factors / metabolism
  • Sequence Analysis, RNA
  • Transcriptome / genetics
  • alpha-Synuclein / metabolism


  • Neurotoxins
  • RBFOX1 protein, human
  • RNA Splicing Factors
  • alpha-Synuclein