A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease
Sci Transl Med. 2020 Sep 9;12(560):eaau3960
| Authors/Editors: |
Boussaad I Obermaier CD Hanss Z Bobbili DR Bolognin S Glaab E Wołyńska K Weisschuh N De Conti L May C Giesert F Grossmann D Lambert A Kirchen S Biryukov M Burbulla LF Massart F Bohler J Cruciani G Schmid B Kurz-Drexler A May P Duga S Klein C Schwamborn JC Marcus K Woitalla D Vogt Weisenhorn DM Wurst W Barrale M Krainc D Gasser T Wissinger B Krüger R |
|---|---|
| Publication Date: | 2020 |
| Type of Publication: | Journal Article |
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.
