Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation
Abstract Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal l...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-04-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-04813-2 |
| _version_ | 1797840870570983424 |
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| author | Daria Messelodi Silvia Strocchi Salvatore Nicola Bertuccio Pascale Baden Valentina Indio Federico M. Giorgi Alberto Taddia Salvatore Serravalle Sabrina Valente Alessio di Fonzo Emanuele Frattini Roberto Bernardoni Annalisa Pession Daniela Grifoni Michela Deleidi Annalisa Astolfi Andrea Pession |
| author_facet | Daria Messelodi Silvia Strocchi Salvatore Nicola Bertuccio Pascale Baden Valentina Indio Federico M. Giorgi Alberto Taddia Salvatore Serravalle Sabrina Valente Alessio di Fonzo Emanuele Frattini Roberto Bernardoni Annalisa Pession Daniela Grifoni Michela Deleidi Annalisa Astolfi Andrea Pession |
| author_sort | Daria Messelodi |
| collection | DOAJ |
| description | Abstract Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD. |
| first_indexed | 2024-04-09T16:21:48Z |
| format | Article |
| id | doaj.art-9bd17c548d7444108e9aef7cad700e02 |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-04-09T16:21:48Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-9bd17c548d7444108e9aef7cad700e022023-04-23T11:25:40ZengNature PortfolioCommunications Biology2399-36422023-04-016111310.1038/s42003-023-04813-2Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activationDaria Messelodi0Silvia Strocchi1Salvatore Nicola Bertuccio2Pascale Baden3Valentina Indio4Federico M. Giorgi5Alberto Taddia6Salvatore Serravalle7Sabrina Valente8Alessio di Fonzo9Emanuele Frattini10Roberto Bernardoni11Annalisa Pession12Daniela Grifoni13Michela Deleidi14Annalisa Astolfi15Andrea Pession16Department of Medical and Surgical Sciences, University of BolognaLaboratory of Translational Research, USL-IRCCS of Reggio EmiliaDepartment of Medical and Surgical Sciences, University of BolognaGerman Center for Neurodegenerative Diseases (DZNE)Department of Veterinary Medical Sciences, University of BolognaDepartment of Pharmacy and Biotechnology, University of BolognaDepartment of Medical and Surgical Sciences, University of BolognaPediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di BolognaDepartment of Medical and Surgical Sciences, University of BolognaNeurology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoNeurology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoDepartment of Pharmacy and Biotechnology, University of BolognaAlma Mater University of BolognaDepartment of Life, Health and Environmental Sciences (MeSVA), University of L’AquilaHertie Institut for Clinical Brain Research, University of TübingenDepartment of Medical and Surgical Sciences, University of BolognaPediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di BolognaAbstract Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD.https://doi.org/10.1038/s42003-023-04813-2 |
| spellingShingle | Daria Messelodi Silvia Strocchi Salvatore Nicola Bertuccio Pascale Baden Valentina Indio Federico M. Giorgi Alberto Taddia Salvatore Serravalle Sabrina Valente Alessio di Fonzo Emanuele Frattini Roberto Bernardoni Annalisa Pession Daniela Grifoni Michela Deleidi Annalisa Astolfi Andrea Pession Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation Communications Biology |
| title | Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation |
| title_full | Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation |
| title_fullStr | Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation |
| title_full_unstemmed | Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation |
| title_short | Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation |
| title_sort | neuronopathic gaucher disease models reveal defects in cell growth promoted by hippo pathway activation |
| url | https://doi.org/10.1038/s42003-023-04813-2 |
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