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

Ibrahim Boussaad; Carolin D. Obermaier; Zoè Hanss; Dheeraj R. Bobbili; Silvia Bolognin; Enrico Glaab; Katarzyna Wolynska; Nicole Weisschuh; Laura De Conti; Caroline May; Florian Giesert; Dajana Grossmann; Annika Lambert; Susanne Kirchen; Maria Biryukov; Lena F. Burbulla; Francois Massart; Jill Bohler; Gèrald Cruciani; Benjamin Schmid; Annerose Kurz-Drexler; Patrick May; Stefano Duga; Christine Klein; Jens C. Schwamborn; Katrin Marcus; Dirk Woitalla; Daniela M.Vogt Weisenhorn; Wolfgang Wurst; Marco Baralle; Dimitri Krainc; Thomas Gasser; Bernd Wissinger; Rejko Krüger

doi:10.1126/SCITRANSLMED.AAU3960

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

Ibrahim Boussaad, Carolin D. Obermaier, Zoè Hanss, Dheeraj R. Bobbili, Silvia Bolognin, Enrico Glaab, Katarzyna Wolynska, Nicole Weisschuh, Laura De Conti, Caroline May, Florian Giesert, Dajana Grossmann, Annika Lambert, Susanne Kirchen, Maria Biryukov, Lena F. Burbulla, Francois Massart, Jill Bohler, Gèrald Cruciani, Benjamin SchmidAnnerose Kurz-Drexler, Patrick May, Stefano Duga, Christine Klein, Jens C. Schwamborn, Katrin Marcus, Dirk Woitalla, Daniela M.Vogt Weisenhorn, Wolfgang Wurst, Marco Baralle, Dimitri Krainc, Thomas Gasser, Bernd Wissinger, Rejko Krüger^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

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.

Original language	English (US)
Article number	eaau3960
Journal	Science translational medicine
Volume	12
Issue number	560
DOIs	https://doi.org/10.1126/SCITRANSLMED.AAU3960
State	Published - Sep 2020

Funding

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 Durchführung 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.

ASJC Scopus subject areas

General Medicine

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Boussaad, I., Obermaier, C. D., Hanss, Z., Bobbili, D. R., Bolognin, S., Glaab, E., Wolynska, 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., ... Krüger, R. (2020). A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease. Science translational medicine, 12(560), Article eaau3960. https://doi.org/10.1126/SCITRANSLMED.AAU3960

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title = "A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease",

abstract = "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.",

author = "Ibrahim Boussaad and Obermaier, {Carolin D.} and Zo{\`e} Hanss and Bobbili, {Dheeraj R.} and Silvia Bolognin and Enrico Glaab and Katarzyna Wolynska and Nicole Weisschuh and {De Conti}, Laura and Caroline May and Florian Giesert and Dajana Grossmann and Annika Lambert and Susanne Kirchen and Maria Biryukov and Burbulla, {Lena F.} and Francois Massart and Jill Bohler and G{\`e}rald Cruciani and Benjamin Schmid and Annerose Kurz-Drexler and Patrick May and Stefano Duga and Christine Klein and Schwamborn, {Jens C.} and Katrin Marcus and Dirk Woitalla and Weisenhorn, {Daniela M.Vogt} and Wolfgang Wurst and Marco Baralle and Dimitri Krainc and Thomas Gasser and Bernd Wissinger and Rejko Kr{\"u}ger",

note = "Publisher Copyright: Copyright {\textcopyright} 2020 The Authors, some rights reserved.",

year = "2020",

month = sep,

doi = "10.1126/SCITRANSLMED.AAU3960",

language = "English (US)",

volume = "12",

journal = "Science translational medicine",

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Boussaad, I, Obermaier, CD, Hanss, Z, Bobbili, DR, Bolognin, S, Glaab, E, Wolynska, K, Weisschuh, N, De Conti, L, May, C, Giesert, F, Grossmann, D, Lambert, A, Kirchen, S, Biryukov, M, Burbulla, LF, Massart, F, Bohler, J, Cruciani, G, Schmid, B, Kurz-Drexler, A, May, P, Duga, S, Klein, C, Schwamborn, JC, Marcus, K, Woitalla, D, Weisenhorn, DMV, Wurst, W, Baralle, M, Krainc, D, Gasser, T, Wissinger, B & Krüger, R 2020, 'A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease', Science translational medicine, vol. 12, no. 560, eaau3960. https://doi.org/10.1126/SCITRANSLMED.AAU3960

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

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.

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VL - 12

JO - Science translational medicine

JF - Science translational medicine

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

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