Genetic correction of a lrrk2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression

Peter Reinhardt, Benjamin Schmid, Lena F. Burbulla, David C. Schöndorf, Lydia Wagner, Michael Glatza, Susanne Höing, Gunnar Hargus, Susanna A. Heck, Ashutosh Dhingra, Guangming Wu, Stephan Müller, Kathrin Brockmann, Torsten Kluba, Martina Maisel, Rejko Krüger, Daniela Berg, Yaroslav Tsytsyura, Cora S. Thiel, Olympia Ekaterini PsathakiJürgen Klingauf, Tanja Kuhlmann, Marlene Klewin, Heiko Müller, Thomas Gasser*, Hans R. Schöler, Jared Sterneckert

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

336 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)354-367
Number of pages14
JournalCell stem cell
Volume12
Issue number3
DOIs
StatePublished - Mar 7 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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