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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)
Postprint DOI PMC
Open Access Green
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
Corresponding Author
Keywords Lysosomal Dysfunction; Dj-1-deficient Mice; Genetic-variation; Rare; Mutations; Variants; Dj-1; Database; Neurodegeneration; Burden
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
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)