Reference : A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's d...

	Document type :	Scientific journals : Article
	Discipline(s) :	Life sciences : Biotechnology Life sciences : Multidisciplinary, general & others Human health sciences : Neurology
	Focus Areas :	Systems Biomedicine
	To cite this reference:	http://hdl.handle.net/10993/44767

Title :	A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease.
Language :	English
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]
Publication date :	2020
Journal title :	Science translational medicine
Volume :	12
Issue/season :	560
Peer reviewed :	Yes (verified by ORBilu)
Audience :	International
ISSN :	1946-6234
e-ISSN :	1946-6242
Country :	United States
Keywords :	[en] 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 centres :	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)
Funders :	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)
Name of the research project :	R-STR-4019 > Neurology > 01/01/2014 - 19/01/2048 > KRUGER Rejko
Target :	Researchers ; Professionals ; Students
Permalink :	http://hdl.handle.net/10993/44767
DOI :	10.1126/scitranslmed.aau3960
Other URL :	https://stm.sciencemag.org/content/12/560/eaau3960
Framework Programme / European Project :	H2020 ; 692320 - CENTRE-PD - TWINNING for a Comprehensive Clinical Centre for the Diagnosis and Treatment of Parkinson's Disease
FnR project :	FnR ; FNR11264123 > Rejko Krüger > NCER-PD > > 01/01/2015 > 30/11/2020 > 2013

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