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 ![]() | |
Obermaier, Carolin D. [> >] | |
Hanss, Zoé [> >] | |
Bobbili, Dheeraj R. [] | |
Bolognin, Silvia ![]() | |
Glaab, Enrico ![]() | |
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 (CCDH) > Digital Infrastructure] | |
Burbulla, Lena F. [> >] | |
Massart, Francois [> >] | |
Bohler, Jill [> >] | |
Cruciani, Gérald [> >] | |
Schmid, Benjamin [> >] | |
Kurz-Drexler, Annerose [> >] | |
May, Patrick ![]() | |
Duga, Stefano [> >] | |
Klein, Christine [> >] | |
Schwamborn, Jens Christian ![]() | |
Marcus, Katrin [> >] | |
Woitalla, Dirk [> >] | |
Vogt Weisenhorn, Daniela M. [> >] | |
Wurst, Wolfgang [> >] | |
Baralle, Marco [> >] | |
Krainc, Dimitri [> >] | |
Gasser, Thomas [> >] | |
Wissinger, Bernd [> >] | |
Krüger, Rejko ![]() | |
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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