Reference : Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegener...
Scientific journals : Article
Life sciences : Genetics & genetic processes
Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression.
Reinhardt, Peter [> >]
Schmid, Benjamin [> >]
Burbulla, Lena F. [> >]
Schondorf, David C. [> >]
Wagner, Lydia [> >]
Glatza, Michael [> >]
Hoing, Susanne [> >]
Hargus, Gunnar [> >]
Heck, Susanna A. [> >]
Dhingra, Ashutosh [> >]
Wu, Guangming [> >]
Muller, Stephan [> >]
Brockmann, Kathrin [> >]
Kluba, Torsten [> >]
Maisel, Martina [> >]
Krüger, Rejko mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Berg, Daniela [> >]
Tsytsyura, Yaroslav [> >]
Thiel, Cora S. [> >]
Psathaki, Olympia-Ekaterini [> >]
Klingauf, Jurgen [> >]
Kuhlmann, Tanja [> >]
Klewin, Marlene [> >]
Muller, Heiko [> >]
Gasser, Thomas [> >]
Scholer, Hans R. [> >]
Sterneckert, Jared [> >]
Cell Stem Cell
Yes (verified by ORBilu)
United States
[en] Benzamides/pharmacology ; Cell Differentiation/drug effects ; Cells, Cultured ; Diphenylamine/analogs & derivatives/pharmacology ; Dopamine/metabolism ; Extracellular Signal-Regulated MAP Kinases/genetics/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Mutation ; Neurons/cytology/drug effects ; Oxidopamine/pharmacology ; Parkinson Disease/genetics/metabolism ; Protein-Serine-Threonine Kinases/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Rotenone/pharmacology
[en] 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.
Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)
Copyright (c) 2013 Elsevier Inc. All rights reserved.

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