LRRK2 Mutant iPSC-derived DA Neurons Demonstrate Increased Susceptibility to Oxidative Stress

Cell Stem Cell. 2011 Mar 4;8(3):267-80. doi: 10.1016/j.stem.2011.01.013.

Abstract

Studies of Parkinson's disease (PD) have been hindered by lack of access to affected human dopaminergic (DA) neurons. Here, we report generation of induced pluripotent stem cells that carry the p.G2019S mutation (G2019S-iPSCs) in the Leucine-Rich Repeat Kinase-2 (LRRK2) gene, the most common PD-related mutation, and their differentiation into DA neurons. The high penetrance of the LRRK2 mutation and its clinical resemblance to sporadic PD suggest that these cells could provide a valuable platform for disease analysis and drug development. We found that DA neurons derived from G2019S-iPSCs showed increased expression of key oxidative stress-response genes and α-synuclein protein. The mutant neurons were also more sensitive to caspase-3 activation and cell death caused by exposure to stress agents, such as hydrogen peroxide, MG-132, and 6-hydroxydopamine, than control DA neurons. This enhanced stress sensitivity is consistent with existing understanding of early PD phenotypes and represents a potential therapeutic target.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amides / pharmacology
  • Amino Acid Substitution / drug effects
  • Animals
  • Cell Death / drug effects
  • Cell Differentiation / drug effects
  • Dopamine / metabolism*
  • Female
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Leupeptins / pharmacology
  • Mesencephalon / pathology
  • Mice
  • Middle Aged
  • Mutation / genetics*
  • Neurons / drug effects
  • Neurons / pathology*
  • Oxidative Stress* / drug effects
  • Oxidopamine / pharmacology
  • Parkinson Disease / enzymology
  • Parkinson Disease / genetics
  • Parkinson Disease / pathology
  • Phenotype
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyridines / pharmacology
  • rho-Associated Kinases / antagonists & inhibitors
  • rho-Associated Kinases / metabolism

Substances

  • Amides
  • Leupeptins
  • Pyridines
  • Y 27632
  • Oxidopamine
  • Hydrogen Peroxide
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde
  • Dopamine