Genetic Correction of a LRRK2 Mutation in Human iPSCs Links Parkinsonian Neurodegeneration to ERK-Dependent Changes in Gene Expression

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. [Display omitted] ► hiPSC-derived neurons with LRRK2 G2019S exhibit Parkinsonian neurodegeneration ► Genetic correction of the LRRK2 mutation rescued neurodegenerative phenotypes ► Comparative analysis links LRRK2 G2019S, gene dysregulation, and ERK activation ► ERK-dependent gene dysregulation by LRRK2 G2019S contributes to neurodegeneration Comparison of neurons derived from mutant and genetically corrected hiPSCs reveals a role for ERK-mediated regulation of gene expression in neurodegeneration associated with Parkinson’s disease and suggests potential therapeutic avenues.