@article{d475abb733bc43fea3c33388c3623517,
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.",
author = "Peter Reinhardt and Benjamin Schmid and Burbulla, {Lena F.} and Sch{\"o}ndorf, {David C.} and Lydia Wagner and Michael Glatza and Susanne H{\"o}ing and Gunnar Hargus and Heck, {Susanna A.} and Ashutosh Dhingra and Guangming Wu and Stephan M{\"u}ller and Kathrin Brockmann and Torsten Kluba and Martina Maisel and Rejko Kr{\"u}ger and Daniela Berg and Yaroslav Tsytsyura and Thiel, {Cora S.} and Psathaki, {Olympia Ekaterini} and J{\"u}rgen Klingauf and Tanja Kuhlmann and Marlene Klewin and Heiko M{\"u}ller and Thomas Gasser and Sch{\"o}ler, {Hans R.} and Jared Sterneckert",
note = "Funding Information: This work was supported by grants from the German Research (WO 1610/2-1 to M.M. and T.G.; KR2119/8-1 to R.K. and T.G.); Fortuene (Nr. 1831-0-0-0-0 to M.M.); the German Research Council (DFG, KR2119/8-1 to R.K. and T.G.); Fritz Thyssen Foundation (10.11.2.153 to R.K.); the Michael J. Fox Foundation (LRRK2 Biology LEAPS Award, 2012); and by a doctoral scholarship from the charitable Hertie Foundation (to L.F.B.). Plasmids for reprogramming were obtained from Addgene: Addgene plasmids 8449, 8454, 17217, 17218, 17219, and 17220. We would like to acknowledge Ann-Kathrin Hauser for the sequencing analysis. We would like to thank Kerstin Hergarten and Rhea Brintrup for excellent technical support. ",
year = "2013",
month = mar,
day = "7",
doi = "10.1016/j.stem.2013.01.008",
language = "English",
volume = "12",
pages = "354--367",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "3",
}