A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease

Ibrahim Boussaad, Carolin D. Obermaier, Zoè Hanss, Dheeraj R. Bobbili, Silvia Bolognin, Enrico Glaab, Katarzyna Wolynska, Nicole Weisschuh, Laura De Conti, Caroline May, Florian Giesert, Dajana Grossmann, Annika Lambert, Susanne Kirchen, Maria Biryukov, Lena F. Burbulla, Francois Massart, Jill Bohler, Gèrald Cruciani, Benjamin SchmidAnnerose 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-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.

Original languageEnglish (US)
Article numbereaau3960
JournalScience translational medicine
Issue number560
StatePublished - Sep 2020

ASJC Scopus subject areas

  • General Medicine


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