title: Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression.
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.
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Reinhardt
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schmid
authors.forename: Lena F
authors.initials: LF
authors.lastname: Burbulla
authors.forename: David C
authors.initials: DC
authors.lastname: Schöndorf
authors.forename: Lydia
authors.initials: L
authors.lastname: Wagner
authors.forename: Michael
authors.initials: M
authors.lastname: Glatza
authors.forename: Susanne
authors.initials: S
authors.lastname: Höing
authors.forename: Gunnar
authors.initials: G
authors.lastname: Hargus
authors.forename: Susanna A
authors.initials: SA
authors.lastname: Heck
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Dhingra
authors.forename: Guangming
authors.initials: G
authors.lastname: Wu
authors.forename: Stephan
authors.initials: S
authors.lastname: Müller
authors.forename: Kathrin
authors.initials: K
authors.lastname: Brockmann
authors.forename: Torsten
authors.initials: T
authors.lastname: Kluba
authors.forename: Martina
authors.initials: M
authors.lastname: Maisel
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
authors.forename: Daniela
authors.initials: D
authors.lastname: Berg
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Tsytsyura
authors.forename: Cora S
authors.initials: CS
authors.lastname: Thiel
authors.forename: Olympia-Ekaterini
authors.initials: OE
authors.lastname: Psathaki
authors.forename: Jürgen
authors.initials: J
authors.lastname: Klingauf
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuhlmann
authors.forename: Marlene
authors.initials: M
authors.lastname: Klewin
authors.forename: Heiko
authors.initials: H
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: Hans R
authors.initials: HR
authors.lastname: Schöler
authors.forename: Jared
authors.initials: J
authors.lastname: Sterneckert
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012402:Rotenone / Q000494:pharmacology
chemical_list: D001549:Benzamides; D012402:Rotenone; C506614:mirdametinib; D016627:Oxidopamine; D004159:Diphenylamine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D004298:Dopamine