Genetic Correction of a LRRK2 Mutation in Human iPSCs Links Parkinsonian Neurodegeneration to ERK-Dependent Changes in Gene Expression
2013; Elsevier BV; Volume: 12; Issue: 3 Linguagem: Inglês
10.1016/j.stem.2013.01.008
ISSN1934-5909
AutoresPeter 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 A. Müller, Kathrin Brockmann, Torsten Kluba, Martina Maisel, Rejko Krüger, Daniela Berg, Yaroslav Tsytsyura, Cora S. Thiel, Olympia-Ekaterini Psathaki, Jürgen Klingauf, Tanja Kuhlmann, Marlene Klewin, Heiko Müller, Thomas Gasser, Hans R. Schöler, Jared Sterneckert,
Tópico(s)Neurological diseases and metabolism
ResumoSummary 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.
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