Generation of iPSCs carrying a common LRRK2 risk allele for in vitro modeling of idiopathic Parkinson's disease

PLoS One. 2018 Mar 7;13(3):e0192497. doi: 10.1371/journal.pone.0192497. eCollection 2018.

Abstract

Induced pluripotent stem cells (iPSCs) have recapitulated several aspects of Parkinson's disease (PD), but most iPSCs are derived from familial cases, which account for only about 15% of patients. Thus, while the emphasis has justifiably been on using iPSCs to model rare familial cases, models for the most common forms of PD are critically lacking. Here, we report the generation of an iPSC-based model of idiopathic PD (iPD) with or without RS1491923, which is a common risk variant in the LRRK2 locus. Consistent with GWA studies, we found large variability in our datasets. However, iPSC-derived neurons carrying the risk allele emerged for displaying subtle disturbances of cellular degradative systems, in line with familial PD models. We also observed that treatment with the LRRK2 inhibitor CZC-25146 slightly reduced a marker of aSYN pathology in all iPD lines. Future iPSC-based studies may need to be structured similarly to large GWA studies in order to obtain relevant statistical power. However, results from this pilot study suggest that iPSC-based modeling represents an attractive way to investigate idiopathic diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics*
  • Male
  • Middle Aged
  • Models, Genetic
  • Parkinson Disease / genetics*
  • Parkinson Disease / pathology
  • Pilot Projects
  • Polymorphism, Single Nucleotide*
  • Risk Factors

Substances

  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2

Grants and funding

Lara Marrone was sponsored by a fellowship from the Hans and Ilse Breuer Stiftung. This work was supported by a grant from the Michael J. Fox Foundation for Parkinson’s Research, GA 402/18-1 from the Deutsche Forschungsgemeinschaft (DFG) awarded to both T.G. and J.S. as well as by DFG Research Center (DFG FZ 111) and Cluster of Excellence (DFG EXC 168). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.