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Boussaad, I.* ; Obermaier, C.D.* ; Hanss, Z.* ; Bobbili, D.R.* ; Bolognin, S.* ; Glaab, E.* ; Wołyńska, K.* ; Weisschuh, N.* ; De Conti, L.* ; May, C.* ; Giesert, F. ; Grossmann, D.* ; Lambert, A.* ; Kirchen, S.* ; Biryukov, M.* ; Burbulla, L.F.* ; Massart, F.* ; Bohler, J.* ; Cruciani, G.* ; Schmid, B.* ; Kurz-Drexler, A. ; May, P.* ; Duga, S.* ; Klein, C.* ; Schwamborn, J.C.* ; Marcus, K.* ; Woitalla, D.* ; Vogt Weisenhorn, D.M. ; Wurst, W. ; Baralle, M.* ; Krainc, D.* ; Gasser, T.* ; Wissinger, B.* ; Krüger, R.*

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

Sci. Transl. Med. 12:eaau3960 (2020)
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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, mitochondria! 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 mitochondria! 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Lysosomal Dysfunction; Dj-1-deficient Mice; Genetic-variation; Rare; Mutations; Variants; Dj-1; Database; Neurodegeneration; Burden
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 1946-6234
e-ISSN 1946-6242
Journal Science Translational Medicine
Quellenangaben Volume: 12, Issue: 560, Pages: , Article Number: eaau3960 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place 1200 New York Ave, Nw, Washington, Dc 20005 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
POF-Topic(s) 30204 - Cell Programming and Repair
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500500-001
G-500500-009
G-500500-005
DOI 10.1126/scitranslmed.aau3960
WOS ID WOS:000567648900001
Scopus ID 85090816747
PubMed ID 32908004
Erfassungsdatum 2020-11-02
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