Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype
Abstract Batten diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration. We discovered increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and used fluorescent‐conjugate...
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-10-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202013742 |
| _version_ | 1797283330874408960 |
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| author | Chiara Soldati Irene Lopez‐Fabuel Luca G Wanderlingh Marina Garcia‐Macia Jlenia Monfregola Alessandra Esposito Gennaro Napolitano Marta Guevara‐Ferrer Anna Scotto Rosato Einar K Krogsaeter Dominik Paquet Christian M Grimm Sandro Montefusco Thomas Braulke Stephan Storch Sara E Mole Maria A De Matteis Andrea Ballabio Julio L Sampaio Tristan McKay Ludger Johannes Juan P Bolaños Diego L Medina |
| author_facet | Chiara Soldati Irene Lopez‐Fabuel Luca G Wanderlingh Marina Garcia‐Macia Jlenia Monfregola Alessandra Esposito Gennaro Napolitano Marta Guevara‐Ferrer Anna Scotto Rosato Einar K Krogsaeter Dominik Paquet Christian M Grimm Sandro Montefusco Thomas Braulke Stephan Storch Sara E Mole Maria A De Matteis Andrea Ballabio Julio L Sampaio Tristan McKay Ludger Johannes Juan P Bolaños Diego L Medina |
| author_sort | Chiara Soldati |
| collection | DOAJ |
| description | Abstract Batten diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration. We discovered increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and used fluorescent‐conjugated bacterial toxins to label Gb3 to develop a cell‐based high content imaging (HCI) screening assay for the repurposing of FDA‐approved compounds able to reduce this accumulation within BD cells. We found that tamoxifen reduced the lysosomal accumulation of Gb3 in CLN3 and CLN7 cell models, including neuronal progenitor cells (NPCs) from CLN7 patient‐derived induced pluripotent stem cells (iPSC). Here, tamoxifen exerts its action through a mechanism that involves activation of the transcription factor EB (TFEB), a master gene of lysosomal function and autophagy. In vivo administration of tamoxifen to the CLN7Δex2 mouse model reduced the accumulation of Gb3 and SCMAS, decreased neuroinflammation, and improved motor coordination. These data strongly suggest that tamoxifen may be a suitable drug to treat some types of Batten disease. |
| first_indexed | 2024-03-07T17:29:31Z |
| format | Article |
| id | doaj.art-d6c8d9dd375c49b29d6deee58e6d431f |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:29:31Z |
| publishDate | 2021-10-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-d6c8d9dd375c49b29d6deee58e6d431f2024-03-02T18:27:23ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-10-011310n/an/a10.15252/emmm.202013742Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotypeChiara Soldati0Irene Lopez‐Fabuel1Luca G Wanderlingh2Marina Garcia‐Macia3Jlenia Monfregola4Alessandra Esposito5Gennaro Napolitano6Marta Guevara‐Ferrer7Anna Scotto Rosato8Einar K Krogsaeter9Dominik Paquet10Christian M Grimm11Sandro Montefusco12Thomas Braulke13Stephan Storch14Sara E Mole15Maria A De Matteis16Andrea Ballabio17Julio L Sampaio18Tristan McKay19Ludger Johannes20Juan P Bolaños21Diego L Medina22Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli Naples ItalyInstitute of Functional Biology and Genomics CSIC University of Salamanca Salamanca SpainTelethon Institute of Genetics and Medicine (TIGEM), Pozzuoli Naples ItalyInstitute of Functional Biology and Genomics CSIC University of Salamanca Salamanca SpainTelethon Institute of Genetics and Medicine (TIGEM), Pozzuoli Naples ItalyTelethon Institute of Genetics and Medicine (TIGEM), Pozzuoli Naples ItalyTelethon Institute of Genetics and Medicine (TIGEM), Pozzuoli Naples ItalySchool of Healthcare Science Manchester Metropolitan University Manchester UKFaculty of Medicine Walther Straub Institute of Pharmacology and Toxicology Ludwig‐Maximilians University Munich GermanyFaculty of Medicine Walther Straub Institute of Pharmacology and Toxicology Ludwig‐Maximilians University Munich GermanyInstitute for Stroke and Dementia Research (ISD) University Hospital LMU Munich Munich GermanyFaculty of Medicine Walther Straub Institute of Pharmacology and Toxicology Ludwig‐Maximilians University Munich GermanyTelethon Institute of Genetics and Medicine (TIGEM), Pozzuoli Naples ItalyDepartment Osteology & Biomechanics University Medical Center Hamburg‐Eppendorf Hamburg GermanyUniversity Children's Research@Kinder‐UKE University Medical Center Hamburg‐Eppendorf Hamburg GermanyMedical Research Council Laboratory for Molecular Cell Biology and UCL Great Ormond Street Institute of Child Health University College London London UKTelethon Institute of Genetics and Medicine (TIGEM), Pozzuoli Naples ItalyTelethon Institute of Genetics and Medicine (TIGEM), Pozzuoli Naples ItalyCellular and Chemical Biology Department Institut Curie, U1143 INSERM, UMR3666 CNRS PSL Research University Paris FranceSchool of Healthcare Science Manchester Metropolitan University Manchester UKCellular and Chemical Biology Department Institut Curie, U1143 INSERM, UMR3666 CNRS PSL Research University Paris FranceInstitute of Functional Biology and Genomics CSIC University of Salamanca Salamanca SpainTelethon Institute of Genetics and Medicine (TIGEM), Pozzuoli Naples ItalyAbstract Batten diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration. We discovered increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and used fluorescent‐conjugated bacterial toxins to label Gb3 to develop a cell‐based high content imaging (HCI) screening assay for the repurposing of FDA‐approved compounds able to reduce this accumulation within BD cells. We found that tamoxifen reduced the lysosomal accumulation of Gb3 in CLN3 and CLN7 cell models, including neuronal progenitor cells (NPCs) from CLN7 patient‐derived induced pluripotent stem cells (iPSC). Here, tamoxifen exerts its action through a mechanism that involves activation of the transcription factor EB (TFEB), a master gene of lysosomal function and autophagy. In vivo administration of tamoxifen to the CLN7Δex2 mouse model reduced the accumulation of Gb3 and SCMAS, decreased neuroinflammation, and improved motor coordination. These data strongly suggest that tamoxifen may be a suitable drug to treat some types of Batten disease.https://doi.org/10.15252/emmm.202013742CLN3CLN7high content imaging screeningtamoxifenTFEB |
| spellingShingle | Chiara Soldati Irene Lopez‐Fabuel Luca G Wanderlingh Marina Garcia‐Macia Jlenia Monfregola Alessandra Esposito Gennaro Napolitano Marta Guevara‐Ferrer Anna Scotto Rosato Einar K Krogsaeter Dominik Paquet Christian M Grimm Sandro Montefusco Thomas Braulke Stephan Storch Sara E Mole Maria A De Matteis Andrea Ballabio Julio L Sampaio Tristan McKay Ludger Johannes Juan P Bolaños Diego L Medina Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype EMBO Molecular Medicine CLN3 CLN7 high content imaging screening tamoxifen TFEB |
| title | Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype |
| title_full | Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype |
| title_fullStr | Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype |
| title_full_unstemmed | Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype |
| title_short | Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype |
| title_sort | repurposing of tamoxifen ameliorates cln3 and cln7 disease phenotype |
| topic | CLN3 CLN7 high content imaging screening tamoxifen TFEB |
| url | https://doi.org/10.15252/emmm.202013742 |
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