iPSC modeling of young-onset Parkinson's disease reveals a molecular signature of disease and novel therapeutic candidates

Nat Med. 2020 Feb;26(2):289-299. doi: 10.1038/s41591-019-0739-1. Epub 2020 Jan 27.


Young-onset Parkinson's disease (YOPD), defined by onset at <50 years, accounts for approximately 10% of all Parkinson's disease cases and, while some cases are associated with known genetic mutations, most are not. Here induced pluripotent stem cells were generated from control individuals and from patients with YOPD with no known mutations. Following differentiation into cultures containing dopamine neurons, induced pluripotent stem cells from patients with YOPD showed increased accumulation of soluble α-synuclein protein and phosphorylated protein kinase Cα, as well as reduced abundance of lysosomal membrane proteins such as LAMP1. Testing activators of lysosomal function showed that specific phorbol esters, such as PEP005, reduced α-synuclein and phosphorylated protein kinase Cα levels while increasing LAMP1 abundance. Interestingly, the reduction in α-synuclein occurred through proteasomal degradation. PEP005 delivery to mouse striatum also decreased α-synuclein production in vivo. Induced pluripotent stem cell-derived dopaminergic cultures reveal a signature in patients with YOPD who have no known Parkinson's disease-related mutations, suggesting that there might be other genetic contributions to this disorder. This signature was normalized by specific phorbol esters, making them promising therapeutic candidates.

Publication types

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

MeSH terms

  • Adult
  • Age of Onset
  • Animals
  • Cell Differentiation / genetics
  • Dopamine / metabolism
  • Dopaminergic Neurons / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Leukocytes, Mononuclear / cytology
  • Lysosomes / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mutation*
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism*
  • Parkinson Disease / therapy*
  • Patch-Clamp Techniques
  • Phenotype
  • Phorbol Esters
  • Phosphorylation
  • Proteomics
  • Transcriptome
  • alpha-Synuclein / metabolism


  • Membrane Proteins
  • Phorbol Esters
  • alpha-Synuclein
  • Dopamine