A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson’s disease
Ibrahim Boussaad, Carolin D. Obermaier, Zoé Hanss, Dheeraj Reddy Bobbili, Silvia Bolognin, Enrico Glaab, Katarzyna Wicher, Nicole Weisschuh, Laura De Conti, Caroline May, Florian Giesert, Dajana Großmann, Annika Lambert, Susanne Kirchen, Maria Biryukov, Lena F. Burbulla, François Massart, Jill Bohler, Gérald Cruciani, Benjamin Schmid, Annerose Kurz-Drexler, Patrick May, Stefano Duga, Christine Klein, Jens C. Schwamborn, Katrin Marcus, Dirk Woitalla, Daniela M. Vogt Weisenhorn, Wolfgang Wurst, Marco Baralle, Dimitri Krainc, Thomas Gasser, Bernd Wissinger, Rejko Krüger
Abstract
-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD.