High content screening and proteomic analysis identify a kinase inhibitor that rescues pathological phenotypes in a patient-derived model of Parkinson’s disease
Abstract Combining high throughput screening approaches with induced pluripotent stem cell (iPSC)-based disease modeling represents a promising unbiased strategy to identify therapies for neurodegenerative disorders. Here we applied high content imaging on iPSC-derived neurons from patients with fam...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-02-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-022-00278-y |
| _version_ | 1797643018549854208 |
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| author | Nasia Antoniou Kanella Prodromidou Georgia Kouroupi Ioanna Boumpoureka Martina Samiotaki George Panayotou Maria Xilouri Ismini Kloukina Leonidas Stefanis Regis Grailhe Era Taoufik Rebecca Matsas |
| author_facet | Nasia Antoniou Kanella Prodromidou Georgia Kouroupi Ioanna Boumpoureka Martina Samiotaki George Panayotou Maria Xilouri Ismini Kloukina Leonidas Stefanis Regis Grailhe Era Taoufik Rebecca Matsas |
| author_sort | Nasia Antoniou |
| collection | DOAJ |
| description | Abstract Combining high throughput screening approaches with induced pluripotent stem cell (iPSC)-based disease modeling represents a promising unbiased strategy to identify therapies for neurodegenerative disorders. Here we applied high content imaging on iPSC-derived neurons from patients with familial Parkinson’s disease bearing the G209A (p.A53T) α-synuclein (αSyn) mutation and launched a screening campaign on a small kinase inhibitor library. We thus identified the multi-kinase inhibitor BX795 that at a single dose effectively restores disease-associated neurodegenerative phenotypes. Proteomics profiling mapped the molecular pathways underlying the protective effects of BX795, comprising a cohort of 118 protein-mediators of the core biological processes of RNA metabolism, protein synthesis, modification and clearance, and stress response, all linked to the mTORC1 signaling hub. In agreement, expression of human p.A53T-αSyn in neuronal cells affected key components of the mTORC1 pathway resulting in aberrant protein synthesis that was restored in the presence of BX795 with concurrent facilitation of autophagy. Taken together, we have identified a promising small molecule with neuroprotective actions as candidate therapeutic for PD and other protein conformational disorders. |
| first_indexed | 2024-03-11T14:08:36Z |
| format | Article |
| id | doaj.art-cea8d1232e85465989ceec532c924bc4 |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-11T14:08:36Z |
| publishDate | 2022-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-cea8d1232e85465989ceec532c924bc42023-11-02T01:04:19ZengNature Portfolionpj Parkinson's Disease2373-80572022-02-018111810.1038/s41531-022-00278-yHigh content screening and proteomic analysis identify a kinase inhibitor that rescues pathological phenotypes in a patient-derived model of Parkinson’s diseaseNasia Antoniou0Kanella Prodromidou1Georgia Kouroupi2Ioanna Boumpoureka3Martina Samiotaki4George Panayotou5Maria Xilouri6Ismini Kloukina7Leonidas Stefanis8Regis Grailhe9Era Taoufik10Rebecca Matsas11Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur InstituteLaboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur InstituteLaboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur InstituteLaboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur InstituteInstitute of Bioinnovation, Biomedical Sciences Research Center “Alexander Fleming”Institute of Bioinnovation, Biomedical Sciences Research Center “Alexander Fleming”Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA)Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA)Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA)Technology Development Platform, Screening Sciences & Novel Assay Technology, Institut Pasteur KoreaLaboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur InstituteLaboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur InstituteAbstract Combining high throughput screening approaches with induced pluripotent stem cell (iPSC)-based disease modeling represents a promising unbiased strategy to identify therapies for neurodegenerative disorders. Here we applied high content imaging on iPSC-derived neurons from patients with familial Parkinson’s disease bearing the G209A (p.A53T) α-synuclein (αSyn) mutation and launched a screening campaign on a small kinase inhibitor library. We thus identified the multi-kinase inhibitor BX795 that at a single dose effectively restores disease-associated neurodegenerative phenotypes. Proteomics profiling mapped the molecular pathways underlying the protective effects of BX795, comprising a cohort of 118 protein-mediators of the core biological processes of RNA metabolism, protein synthesis, modification and clearance, and stress response, all linked to the mTORC1 signaling hub. In agreement, expression of human p.A53T-αSyn in neuronal cells affected key components of the mTORC1 pathway resulting in aberrant protein synthesis that was restored in the presence of BX795 with concurrent facilitation of autophagy. Taken together, we have identified a promising small molecule with neuroprotective actions as candidate therapeutic for PD and other protein conformational disorders.https://doi.org/10.1038/s41531-022-00278-y |
| spellingShingle | Nasia Antoniou Kanella Prodromidou Georgia Kouroupi Ioanna Boumpoureka Martina Samiotaki George Panayotou Maria Xilouri Ismini Kloukina Leonidas Stefanis Regis Grailhe Era Taoufik Rebecca Matsas High content screening and proteomic analysis identify a kinase inhibitor that rescues pathological phenotypes in a patient-derived model of Parkinson’s disease npj Parkinson's Disease |
| title | High content screening and proteomic analysis identify a kinase inhibitor that rescues pathological phenotypes in a patient-derived model of Parkinson’s disease |
| title_full | High content screening and proteomic analysis identify a kinase inhibitor that rescues pathological phenotypes in a patient-derived model of Parkinson’s disease |
| title_fullStr | High content screening and proteomic analysis identify a kinase inhibitor that rescues pathological phenotypes in a patient-derived model of Parkinson’s disease |
| title_full_unstemmed | High content screening and proteomic analysis identify a kinase inhibitor that rescues pathological phenotypes in a patient-derived model of Parkinson’s disease |
| title_short | High content screening and proteomic analysis identify a kinase inhibitor that rescues pathological phenotypes in a patient-derived model of Parkinson’s disease |
| title_sort | high content screening and proteomic analysis identify a kinase inhibitor that rescues pathological phenotypes in a patient derived model of parkinson s disease |
| url | https://doi.org/10.1038/s41531-022-00278-y |
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