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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Lara Marrone - , TUD Dresden University of Technology (Author)
  • Christine Bus - , University of Tübingen, German Center for Neurodegenerative Diseases (DZNE) (Author)
  • David Schöndorf - , University of Tübingen, German Center for Neurodegenerative Diseases (DZNE) (Author)
  • Julia Catherine Fitzgerald - , University of Tübingen, German Center for Neurodegenerative Diseases (DZNE) (Author)
  • Manuela Kübler - , University of Tübingen, German Center for Neurodegenerative Diseases (DZNE) (Author)
  • Benjamin Schmid - , University of Tübingen, Bioneer A/S (Author)
  • Peter Reinhardt - , TUD Dresden University of Technology, AbbVie (Author)
  • Lydia Reinhardt - , TUD Dresden University of Technology, Max Planck Institute for Molecular Biomedicine (Author)
  • Michela Deleidi - , University of Tübingen, German Center for Neurodegenerative Diseases (DZNE) (Author)
  • Tanya Levin - , TUD Dresden University of Technology (Author)
  • Andrea Meixner - , German Center for Neurodegenerative Diseases (DZNE) (Author)
  • Barbara Klink - , TUD Dresden University of Technology (Author)
  • Michael Glatza - , TUD Dresden University of Technology, Max Planck Institute for Molecular Biomedicine (Author)
  • Christian Johannes Gloeckner - , German Center for Neurodegenerative Diseases (DZNE), University of Tübingen (Author)
  • Thomas Gasser - , University of Tübingen, German Center for Neurodegenerative Diseases (DZNE) (Author)
  • Jared Sterneckert - , iPS Cells and Neurodegenerative Disease (Junior Research Group) (Author)

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.

Details

Original languageEnglish
Article numbere0192497
JournalPloS one
Volume13
Issue number3
Publication statusPublished - Mar 2018
Peer-reviewedYes

External IDs

PubMed 29513666
ORCID /0000-0002-7688-3124/work/142250032

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