Article (Scientific journals)
A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease.
Boussaad, Ibrahim; Obermaier, Carolin D.; Hanss, Zoé et al.
2020In Science Translational Medicine, 12 (560)
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Keywords :
Parkinson's disease; splicing; RNA; drug; in-vitro model; organoid; neuroprotection; precision medicine
Abstract :
[en] 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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
- Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group)
- Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group)
- Luxembourg Centre for Contemporary and Digital History (C2DH) > Digital Research Infrastructure (DRI)
Disciplines :
Life sciences: Multidisciplinary, general & others
Biotechnology
Neurology
Author, co-author :
Boussaad, Ibrahim ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Obermaier, Carolin D.
Hanss, Zoé
Bobbili, Dheeraj R.
Bolognin, Silvia ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
Glaab, Enrico  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Biomedical Data Science
Wołyńska, Katarzyna
Weisschuh, Nicole
De Conti, Laura
May, Caroline
Giesert, Florian
Grossmann, Dajana
Lambert, Annika
Kirchen, Susanne
Biryukov, Maria ;  University of Luxembourg > Luxembourg Centre for Contemporary and Digital History (C2DH) > Digital Infrastructure
Burbulla, Lena F.
Massart, Francois
Bohler, Jill
Cruciani, Gérald
Schmid, Benjamin
Kurz-Drexler, Annerose
May, Patrick  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Duga, Stefano
Klein, Christine
Schwamborn, Jens Christian ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
Marcus, Katrin
Woitalla, Dirk
Vogt Weisenhorn, Daniela M.
Wurst, Wolfgang
Baralle, Marco
Krainc, Dimitri
Gasser, Thomas
Wissinger, Bernd
Krüger, Rejko ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
More authors (24 more) Less
External co-authors :
yes
Language :
English
Title :
A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease.
Publication date :
2020
Journal title :
Science Translational Medicine
ISSN :
1946-6242
Publisher :
American Association for the Advancement of Science, United States
Volume :
12
Issue :
560
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
European Projects :
H2020 - 692320 - CENTRE-PD - TWINNING for a Comprehensive Clinical Centre for the Diagnosis and Treatment of Parkinson's Disease
FnR Project :
FNR11264123 - Ncer-pd, 2015 (01/01/2015-30/11/2020) - Rejko Krüger
Name of the research project :
R-STR-4019-00 > Neurology > 01/01/2014 - 19/01/2048 > KRUGER Rejko
Funders :
FNR - Fonds National de la Recherche [LU]
German Research Council
EU Joint Program-Neurodegenerative Diseases
European Union Horizon2020 research and innovation programme
NIH - National Institutes of Health [US-MD]
CE - Commission Européenne [BE]
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