PuSH - Publikationsserver des Helmholtz Zentrums München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
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)
Verlagsversion Postprint Forschungsdaten 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.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Scopus
Cited By
Altmetric
16.304
3.022
2
9
Tags
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern

Zusatzinfos bearbeiten
Eigene Tags bearbeiten
Privat
Eigene Anmerkung bearbeiten
Privat
Auf Publikationslisten für
Homepage nicht anzeigen
Als besondere Publikation
markieren
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Lysosomal Dysfunction; Dj-1-deficient Mice; Genetic-variation; Rare; Mutations; Variants; Dj-1; Database; Neurodegeneration; Burden
Sprache englisch
Veröffentlichungsjahr 2020
HGF-Berichtsjahr 2020
ISSN (print) / ISBN 1946-6234
e-ISSN 1946-6242
Zeitschrift Science Translational Medicine
Quellenangaben Band: 12, Heft: 560, Seiten: , Artikelnummer: eaau3960 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort 1200 New York Ave, Nw, Washington, Dc 20005 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Developmental Genetics (IDG)
POF Topic(s) 30204 - Cell Programming and Repair
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) 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
[➜Korrektur melden]