Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression

Cell Stem Cell. 2013 Mar 7;12(3):354-67. doi: 10.1016/j.stem.2013.01.008.

Abstract

The LRRK2 mutation G2019S is the most common genetic cause of Parkinson's disease (PD). To better understand the link between mutant LRRK2 and PD pathology, we derived induced pluripotent stem cells from PD patients harboring LRRK2 G2019S and then specifically corrected the mutant LRRK2 allele. We demonstrate that gene correction resulted in phenotypic rescue in differentiated neurons and uncovered expression changes associated with LRRK2 G2019S. We found that LRRK2 G2019S induced dysregulation of CPNE8, MAP7, UHRF2, ANXA1, and CADPS2. Knockdown experiments demonstrated that four of these genes contribute to dopaminergic neurodegeneration. LRRK2 G2019S induced increased extracellular-signal-regulated kinase 1/2 (ERK) phosphorylation. Transcriptional dysregulation of CADPS2, CPNE8, and UHRF2 was dependent on ERK activity. We show that multiple PD-associated phenotypes were ameliorated by inhibition of ERK. Therefore, our results provide mechanistic insight into the pathogenesis induced by mutant LRRK2 and pointers for the development of potential new therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides / pharmacology
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / pharmacology
  • Dopamine / metabolism
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mutation
  • Neurons / cytology
  • Neurons / drug effects
  • Oxidopamine / pharmacology
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism*
  • Protein-Serine-Threonine Kinases / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rotenone / pharmacology

Substances

  • Benzamides
  • PD 0325901
  • Rotenone
  • Oxidopamine
  • Diphenylamine
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Dopamine