TY - JOUR
T1 - A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease
AU - Boussaad, Ibrahim
AU - Obermaier, Carolin D.
AU - Hanss, Zoè
AU - Bobbili, Dheeraj R.
AU - Bolognin, Silvia
AU - Glaab, Enrico
AU - Wolynska, Katarzyna
AU - Weisschuh, Nicole
AU - De Conti, Laura
AU - May, Caroline
AU - Giesert, Florian
AU - Grossmann, Dajana
AU - Lambert, Annika
AU - Kirchen, Susanne
AU - Biryukov, Maria
AU - Burbulla, Lena F.
AU - Massart, Francois
AU - Bohler, Jill
AU - Cruciani, Gèrald
AU - Schmid, Benjamin
AU - Kurz-Drexler, Annerose
AU - May, Patrick
AU - Duga, Stefano
AU - Klein, Christine
AU - Schwamborn, Jens C.
AU - Marcus, Katrin
AU - Woitalla, Dirk
AU - Weisenhorn, Daniela M.Vogt
AU - Wurst, Wolfgang
AU - Baralle, Marco
AU - Krainc, Dimitri
AU - Gasser, Thomas
AU - Wissinger, Bernd
AU - Krüger, Rejko
N1 - Funding Information:
This work was supported by grants from the Luxembourg National Research Fund (FNR) within the PEARL programme (FNR; FNR/P13/6682797 to R.K.), the German Research Council (DFG; KR2119/8-1 to R.K. and T.G. and KL1134/11-1 to C.K.), the EU Joint Program-Neurodegenerative Diseases (JPND; COURAGE-PD to E.G., D.R.B., P.M., R.K., C.K., and T.G.; 3DPD to J.C.S.), and the European Union's Horizon2020 research and innovation program under grant agreement no. 692320 (WIDESPREAD; CENTRE-PD to R.K.). This work was supported by NIH grants R01NS076054 and R37 NS096241 (to D.K.). The work was supported by the Luxembourg National Research Fund (FNR; grant no. C13/BM/5782168) to E.G. Works of C.M. and K.M. were supported by the HUPO Brain Proteome Project, PURE (a project of Nordrhein-Westfalen, a federal German state), the Deutsche Parkinson Gesellschaft e.V., and the Verein zur Durchf?hrung Neurowissenschaftlicher Tagungen e.V. (Berlin, Germany). Work was supported by the German Science Foundation Collaborative Research Centre (CRC 870to W.W.) on "DJ-1 Linked Neurodegeneration Pathways in New Mouse Models of Parkinson's Disease" (WU 164/5-1 to W.W.); Munich Cluster for Systems Neurology (EXC 1010 SyNergy to W.W.); the Bavarian Ministry of Education, Culture and Science [Human Induced Pluripotent Stem Cells (ForIPS)]; the Helmholtz Portfolio Theme "Supercomputing and Modelling for the Human Brain" (SMHB); and the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept MitoPD (grant 031A430E to W.W.). C.K. is the recipient of a career development award from the Hermann and Lilly Schilling Foundation.
Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved.
PY - 2020/9
Y1 - 2020/9
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85090816747
U2 - 10.1126/SCITRANSLMED.AAU3960
DO - 10.1126/SCITRANSLMED.AAU3960
M3 - Article
C2 - 32908004
AN - SCOPUS:85090816747
SN - 1946-6234
VL - 12
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 560
M1 - eaau3960
ER -