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1. Induced pluripotent stem cell line (LCSBi001-A) derived from a patient with Parkinson's disease carrying the p.D620N mutation in VPS35

Author

Fonds National de la Recherche - FnR [sponsor], H2020 [sponsor], Larsen, Simone, Hanss, Zoé, Cruciani, Gérald, Massart, François, Barbuti, Peter, Mellick, George, Krüger, Rejko, Fonds National de la Recherche - FnR [sponsor], H2020 [sponsor], Larsen, Simone, Hanss, Zoé, Cruciani, Gérald, Massart, François, Barbuti, Peter, Mellick, George, and Krüger, Rejko

Abstract

Fibroblasts were obtained from a 76 year-old man diagnosed with Parkinson's disease (PD). The disease is caused by a heterozygous p.D620N mutation in VPS35. Induced pluripotent stem cells (iPSCs) were generated using the CytoTune™-iPS 2.0 Sendai Reprogramming Kit (Thermo Fisher Scientific). The presence of the c.1858G > A base exchange in exon 15 of VPS35 was confirmed by Sanger sequencing. The iPSCs are free of genomically integrated reprogramming genes, express pluripotency markers, display in vitro differentiation potential to the three germ layers and have karyotypic integrity. Our iPSC line will be useful for studying the impact of the p.D620N mutation in VPS35 in vitro.

Published
2020

2. Induced pluripotent stem cell line (LCSBi001-A) derived from a patient with Parkinson's disease carrying the p.D620N mutation in VPS35

Author

Fonds National de la Recherche - FnR [sponsor], H2020 [sponsor], Larsen, Simone, Hanss, Zoé, Cruciani, Gérald, Massart, François, Barbuti, Peter, Mellick, George, Krüger, Rejko, Fonds National de la Recherche - FnR [sponsor], H2020 [sponsor], Larsen, Simone, Hanss, Zoé, Cruciani, Gérald, Massart, François, Barbuti, Peter, Mellick, George, and Krüger, Rejko

Abstract

Fibroblasts were obtained from a 76 year-old man diagnosed with Parkinson's disease (PD). The disease is caused by a heterozygous p.D620N mutation in VPS35. Induced pluripotent stem cells (iPSCs) were generated using the CytoTune™-iPS 2.0 Sendai Reprogramming Kit (Thermo Fisher Scientific). The presence of the c.1858G > A base exchange in exon 15 of VPS35 was confirmed by Sanger sequencing. The iPSCs are free of genomically integrated reprogramming genes, express pluripotency markers, display in vitro differentiation potential to the three germ layers and have karyotypic integrity. Our iPSC line will be useful for studying the impact of the p.D620N mutation in VPS35 in vitro.

Published
2020

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

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center], Luxembourg Centre for Contemporary and Digital History (C2DH) > Digital Research Infrastructure (DRI) [research center], Fonds National de la Recherche - FnR [sponsor], German Research Council [sponsor], EU Joint Program-Neurodegenerative Diseases [sponsor], European Union Horizon2020 research and innovation programme [sponsor], National Institutes of Health (NIH) [sponsor], Boussaad, Ibrahim, Obermaier, Carolin D., Hanss, Zoé, Bobbili, Dheeraj R., Bolognin, Silvia, Glaab, Enrico, Wołyńska, Katarzyna, Weisschuh, Nicole, De Conti, Laura, May, Caroline, Giesert, Florian, Grossmann, Dajana, Lambert, Annika, Kirchen, Susanne, Biryukov, Maria, Burbulla, Lena F., Massart, Francois, Bohler, Jill, Cruciani, Gérald, Schmid, Benjamin, Kurz-Drexler, Annerose, May, Patrick, Duga, Stefano, Klein, Christine, Schwamborn, Jens Christian, Marcus, Katrin, Woitalla, Dirk, Vogt Weisenhorn, Daniela M., Wurst, Wolfgang, Baralle, Marco, Krainc, Dimitri, Gasser, Thomas, Wissinger, Bernd, Krüger, Rejko, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center], Luxembourg Centre for Contemporary and Digital History (C2DH) > Digital Research Infrastructure (DRI) [research center], Fonds National de la Recherche - FnR [sponsor], German Research Council [sponsor], EU Joint Program-Neurodegenerative Diseases [sponsor], European Union Horizon2020 research and innovation programme [sponsor], National Institutes of Health (NIH) [sponsor], Boussaad, Ibrahim, Obermaier, Carolin D., Hanss, Zoé, Bobbili, Dheeraj R., Bolognin, Silvia, Glaab, Enrico, Wołyńska, Katarzyna, Weisschuh, Nicole, De Conti, Laura, May, Caroline, Giesert, Florian, Grossmann, Dajana, Lambert, Annika, Kirchen, Susanne, Biryukov, Maria, Burbulla, Lena F., Massart, Francois, Bohler, Jill, Cruciani, Gérald, Schmid, Benjamin, Kurz-Drexler, Annerose, May, Patrick, Duga, Stefano, Klein, Christine, Schwamborn, Jens Christian, Marcus, Katrin, Woitalla, Dirk, Vogt Weisenhorn, Daniela M., Wurst, Wolfgang, Baralle, Marco, Krainc, Dimitri, Gasser, Thomas, Wissinger, Bernd, and Krüger, Rejko

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.

Published
2020

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

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center], Luxembourg Centre for Contemporary and Digital History (C2DH) > Digital Research Infrastructure (DRI) [research center], Fonds National de la Recherche - FnR [sponsor], German Research Council [sponsor], EU Joint Program-Neurodegenerative Diseases [sponsor], European Union Horizon2020 research and innovation programme [sponsor], National Institutes of Health (NIH) [sponsor], Boussaad, Ibrahim, Obermaier, Carolin D., Hanss, Zoé, Bobbili, Dheeraj R., Bolognin, Silvia, Glaab, Enrico, Wołyńska, Katarzyna, Weisschuh, Nicole, De Conti, Laura, May, Caroline, Giesert, Florian, Grossmann, Dajana, Lambert, Annika, Kirchen, Susanne, Biryukov, Maria, Burbulla, Lena F., Massart, Francois, Bohler, Jill, Cruciani, Gérald, Schmid, Benjamin, Kurz-Drexler, Annerose, May, Patrick, Duga, Stefano, Klein, Christine, Schwamborn, Jens Christian, Marcus, Katrin, Woitalla, Dirk, Vogt Weisenhorn, Daniela M., Wurst, Wolfgang, Baralle, Marco, Krainc, Dimitri, Gasser, Thomas, Wissinger, Bernd, Krüger, Rejko, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center], Luxembourg Centre for Contemporary and Digital History (C2DH) > Digital Research Infrastructure (DRI) [research center], Fonds National de la Recherche - FnR [sponsor], German Research Council [sponsor], EU Joint Program-Neurodegenerative Diseases [sponsor], European Union Horizon2020 research and innovation programme [sponsor], National Institutes of Health (NIH) [sponsor], Boussaad, Ibrahim, Obermaier, Carolin D., Hanss, Zoé, Bobbili, Dheeraj R., Bolognin, Silvia, Glaab, Enrico, Wołyńska, Katarzyna, Weisschuh, Nicole, De Conti, Laura, May, Caroline, Giesert, Florian, Grossmann, Dajana, Lambert, Annika, Kirchen, Susanne, Biryukov, Maria, Burbulla, Lena F., Massart, Francois, Bohler, Jill, Cruciani, Gérald, Schmid, Benjamin, Kurz-Drexler, Annerose, May, Patrick, Duga, Stefano, Klein, Christine, Schwamborn, Jens Christian, Marcus, Katrin, Woitalla, Dirk, Vogt Weisenhorn, Daniela M., Wurst, Wolfgang, Baralle, Marco, Krainc, Dimitri, Gasser, Thomas, Wissinger, Bernd, and Krüger, Rejko

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.

Published
2020

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

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center], Luxembourg Centre for Contemporary and Digital History (C2DH) > Digital Research Infrastructure (DRI) [research center], Fonds National de la Recherche - FnR [sponsor], German Research Council [sponsor], EU Joint Program-Neurodegenerative Diseases [sponsor], European Union Horizon2020 research and innovation programme [sponsor], National Institutes of Health (NIH) [sponsor], Boussaad, Ibrahim, Obermaier, Carolin D., Hanss, Zoé, Bobbili, Dheeraj R., Bolognin, Silvia, Glaab, Enrico, Wołyńska, Katarzyna, Weisschuh, Nicole, De Conti, Laura, May, Caroline, Giesert, Florian, Grossmann, Dajana, Lambert, Annika, Kirchen, Susanne, Biryukov, Maria, Burbulla, Lena F., Massart, Francois, Bohler, Jill, Cruciani, Gérald, Schmid, Benjamin, Kurz-Drexler, Annerose, May, Patrick, Duga, Stefano, Klein, Christine, Schwamborn, Jens Christian, Marcus, Katrin, Woitalla, Dirk, Vogt Weisenhorn, Daniela M., Wurst, Wolfgang, Baralle, Marco, Krainc, Dimitri, Gasser, Thomas, Wissinger, Bernd, Krüger, Rejko, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center], Luxembourg Centre for Contemporary and Digital History (C2DH) > Digital Research Infrastructure (DRI) [research center], Fonds National de la Recherche - FnR [sponsor], German Research Council [sponsor], EU Joint Program-Neurodegenerative Diseases [sponsor], European Union Horizon2020 research and innovation programme [sponsor], National Institutes of Health (NIH) [sponsor], Boussaad, Ibrahim, Obermaier, Carolin D., Hanss, Zoé, Bobbili, Dheeraj R., Bolognin, Silvia, Glaab, Enrico, Wołyńska, Katarzyna, Weisschuh, Nicole, De Conti, Laura, May, Caroline, Giesert, Florian, Grossmann, Dajana, Lambert, Annika, Kirchen, Susanne, Biryukov, Maria, Burbulla, Lena F., Massart, Francois, Bohler, Jill, Cruciani, Gérald, Schmid, Benjamin, Kurz-Drexler, Annerose, May, Patrick, Duga, Stefano, Klein, Christine, Schwamborn, Jens Christian, Marcus, Katrin, Woitalla, Dirk, Vogt Weisenhorn, Daniela M., Wurst, Wolfgang, Baralle, Marco, Krainc, Dimitri, Gasser, Thomas, Wissinger, Bernd, and Krüger, Rejko

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.

Published
2020

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

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center], Luxembourg Centre for Contemporary and Digital History (C2DH) > Digital Research Infrastructure (DRI) [research center], Fonds National de la Recherche - FnR [sponsor], German Research Council [sponsor], EU Joint Program-Neurodegenerative Diseases [sponsor], European Union Horizon2020 research and innovation programme [sponsor], National Institutes of Health (NIH) [sponsor], Boussaad, Ibrahim, Obermaier, Carolin D., Hanss, Zoé, Bobbili, Dheeraj R., Bolognin, Silvia, Glaab, Enrico, Wołyńska, Katarzyna, Weisschuh, Nicole, De Conti, Laura, May, Caroline, Giesert, Florian, Grossmann, Dajana, Lambert, Annika, Kirchen, Susanne, Biryukov, Maria, Burbulla, Lena F., Massart, Francois, Bohler, Jill, Cruciani, Gérald, Schmid, Benjamin, Kurz-Drexler, Annerose, May, Patrick, Duga, Stefano, Klein, Christine, Schwamborn, Jens Christian, Marcus, Katrin, Woitalla, Dirk, Vogt Weisenhorn, Daniela M., Wurst, Wolfgang, Baralle, Marco, Krainc, Dimitri, Gasser, Thomas, Wissinger, Bernd, Krüger, Rejko, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center], Luxembourg Centre for Contemporary and Digital History (C2DH) > Digital Research Infrastructure (DRI) [research center], Fonds National de la Recherche - FnR [sponsor], German Research Council [sponsor], EU Joint Program-Neurodegenerative Diseases [sponsor], European Union Horizon2020 research and innovation programme [sponsor], National Institutes of Health (NIH) [sponsor], Boussaad, Ibrahim, Obermaier, Carolin D., Hanss, Zoé, Bobbili, Dheeraj R., Bolognin, Silvia, Glaab, Enrico, Wołyńska, Katarzyna, Weisschuh, Nicole, De Conti, Laura, May, Caroline, Giesert, Florian, Grossmann, Dajana, Lambert, Annika, Kirchen, Susanne, Biryukov, Maria, Burbulla, Lena F., Massart, Francois, Bohler, Jill, Cruciani, Gérald, Schmid, Benjamin, Kurz-Drexler, Annerose, May, Patrick, Duga, Stefano, Klein, Christine, Schwamborn, Jens Christian, Marcus, Katrin, Woitalla, Dirk, Vogt Weisenhorn, Daniela M., Wurst, Wolfgang, Baralle, Marco, Krainc, Dimitri, Gasser, Thomas, Wissinger, Bernd, and Krüger, Rejko

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.

Published
2020

7. Mitochondria interaction networks show altered topological patterns in Parkinson's disease.

Author

Zanin, Massimiliano, Santos, Bruno F. R., Antony, Paul, Berenguer-Escuder, Clara, Larsen, Simone B., Hanss, Zoé, Barbuti, Peter, Baumuratov, Aidos, Grossmann, Dajana, Capelle, Christophe M., Weber, Joseph, Balling, Rudolf, Ollert, Markus, Krüger, Rejko, Diederich, Nico J., He, Feng, Zanin, Massimiliano, Santos, Bruno F. R., Antony, Paul, Berenguer-Escuder, Clara, Larsen, Simone B., Hanss, Zoé, Barbuti, Peter, Baumuratov, Aidos, Grossmann, Dajana, Capelle, Christophe M., Weber, Joseph, Balling, Rudolf, Ollert, Markus, Krüger, Rejko, Diederich, Nico J., and He, Feng

Abstract

Mitochondrial dysfunction is linked to pathogenesis of Parkinson's disease (PD). However, individual mitochondria-based analyses do not show a uniform feature in PD patients. Since mitochondria interact with each other, we hypothesize that PD-related features might exist in topological patterns of mitochondria interaction networks (MINs). Here we show that MINs formed nonclassical scale-free supernetworks in colonic ganglia both from healthy controls and PD patients; however, altered network topological patterns were observed in PD patients. These patterns were highly correlated with PD clinical scores and a machine-learning approach based on the MIN features alone accurately distinguished between patients and controls with an area-under-curve value of 0.989. The MINs of midbrain dopaminergic neurons (mDANs) derived from several genetic PD patients also displayed specific changes. CRISPR/CAS9-based genome correction of alpha-synuclein point mutations reversed the changes in MINs of mDANs. Our organelle-interaction network analysis opens another critical dimension for a deeper characterization of various complex diseases with mitochondrial dysregulation.

Published
2020

9. Mitochondria interaction networks show altered topological patterns in Parkinson's disease.

Author

Zanin, Massimiliano, Santos, Bruno F. R., Antony, Paul, Berenguer-Escuder, Clara, Larsen, Simone B., Hanss, Zoé, Barbuti, Peter, Baumuratov, Aidos, Grossmann, Dajana, Capelle, Christophe M., Weber, Joseph, Balling, Rudolf, Ollert, Markus, Krüger, Rejko, Diederich, Nico J., He, Feng, Zanin, Massimiliano, Santos, Bruno F. R., Antony, Paul, Berenguer-Escuder, Clara, Larsen, Simone B., Hanss, Zoé, Barbuti, Peter, Baumuratov, Aidos, Grossmann, Dajana, Capelle, Christophe M., Weber, Joseph, Balling, Rudolf, Ollert, Markus, Krüger, Rejko, Diederich, Nico J., and He, Feng

Abstract

Mitochondrial dysfunction is linked to pathogenesis of Parkinson's disease (PD). However, individual mitochondria-based analyses do not show a uniform feature in PD patients. Since mitochondria interact with each other, we hypothesize that PD-related features might exist in topological patterns of mitochondria interaction networks (MINs). Here we show that MINs formed nonclassical scale-free supernetworks in colonic ganglia both from healthy controls and PD patients; however, altered network topological patterns were observed in PD patients. These patterns were highly correlated with PD clinical scores and a machine-learning approach based on the MIN features alone accurately distinguished between patients and controls with an area-under-curve value of 0.989. The MINs of midbrain dopaminergic neurons (mDANs) derived from several genetic PD patients also displayed specific changes. CRISPR/CAS9-based genome correction of alpha-synuclein point mutations reversed the changes in MINs of mDANs. Our organelle-interaction network analysis opens another critical dimension for a deeper characterization of various complex diseases with mitochondrial dysregulation.

Published
2020

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

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center], Luxembourg Centre for Contemporary and Digital History (C2DH) > Digital Research Infrastructure (DRI) [research center], Fonds National de la Recherche - FnR [sponsor], German Research Council [sponsor], EU Joint Program-Neurodegenerative Diseases [sponsor], European Union Horizon2020 research and innovation programme [sponsor], National Institutes of Health (NIH) [sponsor], Boussaad, Ibrahim, Obermaier, Carolin D., Hanss, Zoé, Bobbili, Dheeraj R., Bolognin, Silvia, Glaab, Enrico, Wołyńska, Katarzyna, Weisschuh, Nicole, De Conti, Laura, May, Caroline, Giesert, Florian, Grossmann, Dajana, Lambert, Annika, Kirchen, Susanne, Biryukov, Maria, Burbulla, Lena F., Massart, Francois, Bohler, Jill, Cruciani, Gérald, Schmid, Benjamin, Kurz-Drexler, Annerose, May, Patrick, Duga, Stefano, Klein, Christine, Schwamborn, Jens Christian, Marcus, Katrin, Woitalla, Dirk, Vogt Weisenhorn, Daniela M., Wurst, Wolfgang, Baralle, Marco, Krainc, Dimitri, Gasser, Thomas, Wissinger, Bernd, Krüger, Rejko, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Developmental and Cellular Biology (Schwamborn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center], Luxembourg Centre for Contemporary and Digital History (C2DH) > Digital Research Infrastructure (DRI) [research center], Fonds National de la Recherche - FnR [sponsor], German Research Council [sponsor], EU Joint Program-Neurodegenerative Diseases [sponsor], European Union Horizon2020 research and innovation programme [sponsor], National Institutes of Health (NIH) [sponsor], Boussaad, Ibrahim, Obermaier, Carolin D., Hanss, Zoé, Bobbili, Dheeraj R., Bolognin, Silvia, Glaab, Enrico, Wołyńska, Katarzyna, Weisschuh, Nicole, De Conti, Laura, May, Caroline, Giesert, Florian, Grossmann, Dajana, Lambert, Annika, Kirchen, Susanne, Biryukov, Maria, Burbulla, Lena F., Massart, Francois, Bohler, Jill, Cruciani, Gérald, Schmid, Benjamin, Kurz-Drexler, Annerose, May, Patrick, Duga, Stefano, Klein, Christine, Schwamborn, Jens Christian, Marcus, Katrin, Woitalla, Dirk, Vogt Weisenhorn, Daniela M., Wurst, Wolfgang, Baralle, Marco, Krainc, Dimitri, Gasser, Thomas, Wissinger, Bernd, and Krüger, Rejko

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.

Published
2020

12. Mitochondria interaction networks show altered topological patterns in Parkinson’s disease

Author

Fonds National de la Recherche Luxembourg, Ministère de l’Enseignement Supérieur et de la Recherche (Luxembourg), European Cooperation in Science and Technology, University of Tübingen, Hertie Institute for Clinical Brain Research, DZNE, European Research Council, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Zanin, Massimiliano, Santos, Bruno F. R., Antony, Paul M. A., Berenguer-Escuder, Clara, Larsen, Simone B., Hanss, Zoé, Barbuti, Peter A., Baumuratov, Aidos S., Grossmann, Dajana, Capelle, Christophe M., Weber, Joseph, Balling, Rudi, Ollert, Markus, Krüger, Rejko, Diederich, Nico J., He, Feng Q., Fonds National de la Recherche Luxembourg, Ministère de l’Enseignement Supérieur et de la Recherche (Luxembourg), European Cooperation in Science and Technology, University of Tübingen, Hertie Institute for Clinical Brain Research, DZNE, European Research Council, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Zanin, Massimiliano, Santos, Bruno F. R., Antony, Paul M. A., Berenguer-Escuder, Clara, Larsen, Simone B., Hanss, Zoé, Barbuti, Peter A., Baumuratov, Aidos S., Grossmann, Dajana, Capelle, Christophe M., Weber, Joseph, Balling, Rudi, Ollert, Markus, Krüger, Rejko, Diederich, Nico J., and He, Feng Q.

Abstract

Mitochondrial dysfunction is linked to pathogenesis of Parkinson’s disease (PD). However, individual mitochondria-based analyses do not show a uniform feature in PD patients. Since mitochondria interact with each other, we hypothesize that PD-related features might exist in topological patterns of mitochondria interaction networks (MINs). Here we show that MINs formed nonclassical scale-free supernetworks in colonic ganglia both from healthy controls and PD patients; however, altered network topological patterns were observed in PD patients. These patterns were highly correlated with PD clinical scores and a machine-learning approach based on the MIN features alone accurately distinguished between patients and controls with an area-under-curve value of 0.989. The MINs of midbrain dopaminergic neurons (mDANs) derived from several genetic PD patients also displayed specific changes. CRISPR/CAS9-based genome correction of alpha-synuclein point mutations reversed the changes in MINs of mDANs. Our organelle-interaction network analysis opens another critical dimension for a deeper characterization of various complex diseases with mitochondrial dysregulation.

Published
2020

15. The genetic architecture of mitochondrial dysfunction in Parkinson's Disease

Author

Luxembourg Centre for Systems Biomedicine (LCSB) [research center], Fonds National de la Recherche - FnR [sponsor], Krüger, Rejko, Larsen, Simone, Hanss, Zoé, Luxembourg Centre for Systems Biomedicine (LCSB) [research center], Fonds National de la Recherche - FnR [sponsor], Krüger, Rejko, Larsen, Simone, and Hanss, Zoé

Abstract

Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson’s disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post mortem brains from sporadic PD patients. Furthermore, several disease-related genes are linked to mitochondrial pathways, such as PRKN, PINK1, DJ-1 and HTRA2 and are associated to mitochondrial impairment. This phenotype can be caused by the dysfunction of mitochondrial quality control machinery at different levels: molecular, organellar or cellular. Mitochondrial unfolded protein response represents the molecular level and implicates various chaperones and proteases. If the molecular level of quality control is not sufficient, the organellar level is required and involves mitophagy and mitochondrial derived vesicles to sequester whole dysfunctional organelle or parts of it. Only when the impairment is too severe, it leads to cell death via apoptosis which defines the cellular level of quality control. Here we review how currently known PD-linked genetic variants interfere with the different levels of mitochondrial quality control. We discuss the graded risk concept of the most recently identified PARK loci (PARK 17-23) and some susceptibility variants such as GBA, LRRK2 and SNCA. Finally, the emerging concept of rare genetic variants as candidates for PD, such as HSPA9, TRAP1 and RHOT1 complete the picture of the complex genetic architecture of PD that will direct future precision medicine approaches.

Published
2018
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16. The genetic architecture of mitochondrial dysfunction in Parkinson's Disease

Author

Luxembourg Centre for Systems Biomedicine (LCSB) [research center], Fonds National de la Recherche - FnR [sponsor], Krüger, Rejko, Larsen, Simone, Hanss, Zoé, Luxembourg Centre for Systems Biomedicine (LCSB) [research center], Fonds National de la Recherche - FnR [sponsor], Krüger, Rejko, Larsen, Simone, and Hanss, Zoé

Abstract

Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson’s disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post mortem brains from sporadic PD patients. Furthermore, several disease-related genes are linked to mitochondrial pathways, such as PRKN, PINK1, DJ-1 and HTRA2 and are associated to mitochondrial impairment. This phenotype can be caused by the dysfunction of mitochondrial quality control machinery at different levels: molecular, organellar or cellular. Mitochondrial unfolded protein response represents the molecular level and implicates various chaperones and proteases. If the molecular level of quality control is not sufficient, the organellar level is required and involves mitophagy and mitochondrial derived vesicles to sequester whole dysfunctional organelle or parts of it. Only when the impairment is too severe, it leads to cell death via apoptosis which defines the cellular level of quality control. Here we review how currently known PD-linked genetic variants interfere with the different levels of mitochondrial quality control. We discuss the graded risk concept of the most recently identified PARK loci (PARK 17-23) and some susceptibility variants such as GBA, LRRK2 and SNCA. Finally, the emerging concept of rare genetic variants as candidates for PD, such as HSPA9, TRAP1 and RHOT1 complete the picture of the complex genetic architecture of PD that will direct future precision medicine approaches.

Published
2018
Full Text
View/download PDF

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