Reference : A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's d...
Scientific journals : Article
Life sciences : Biotechnology
Life sciences : Multidisciplinary, general & others
Human health sciences : Neurology
Systems Biomedicine
http://hdl.handle.net/10993/44767
A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease.
English
Boussaad, Ibrahim mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience]
Obermaier, Carolin D. [> >]
Hanss, Zoé [> >]
Bobbili, Dheeraj R. [> >]
Bolognin, Silvia mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology]
Glaab, Enrico mailto [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 mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core]
Duga, Stefano [> >]
Klein, Christine [> >]
Schwamborn, Jens Christian mailto [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 mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience]
2020
Science translational medicine
12
560
Yes (verified by ORBilu)
International
1946-6234
1946-6242
United States
[en] Parkinson's disease ; splicing ; RNA ; drug ; in-vitro model ; organoid ; neuroprotection ; precision medicine
[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.
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)
Fonds National de la Recherche - FnR ; German Research Council ; EU Joint Program-Neurodegenerative Diseases ; European Union Horizon2020 research and innovation programme ; National Institutes of Health (NIH)
R-STR-4019 > Neurology > 01/01/2014 - 19/01/2048 > KRUGER Rejko
Researchers ; Professionals ; Students
http://hdl.handle.net/10993/44767
10.1126/scitranslmed.aau3960
https://stm.sciencemag.org/content/12/560/eaau3960
H2020 ; 692320 - CENTRE-PD - TWINNING for a Comprehensive Clinical Centre for the Diagnosis and Treatment of Parkinson's Disease
FnR ; FNR11264123 > Rejko Krüger > NCER-PD > > 01/01/2015 > 30/11/2020 > 2013

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