Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome
Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly amelio...
| Autores: | , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:282415 |
| Acceso en línea: | https://ddd.uab.cat/record/282415 https://dx.doi.org/urn:doi:10.7554/eLife.72560 |
| Access Level: | acceso abierto |
| Palabra clave: | Williams-Beuren syndrome Intellectual disability Endocannabinoid system Cannabinoid type-1 receptor Mouse |
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España |
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| dc.title.none.fl_str_mv |
Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome |
| title |
Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome |
| spellingShingle |
Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome Navarro-Romero, Alba Williams-Beuren syndrome Intellectual disability Endocannabinoid system Cannabinoid type-1 receptor Mouse |
| title_short |
Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome |
| title_full |
Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome |
| title_fullStr |
Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome |
| title_full_unstemmed |
Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome |
| title_sort |
Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome |
| dc.creator.none.fl_str_mv |
Navarro-Romero, Alba Galera-López, Lorena Ortiz-Romero, Paula|||0000-0002-6378-6763 Llorente-Ovejero, Alberto de los Reyes-Ramírez, Lucía Bengoetxea de Tena, Iker Garcia-Elias, Anna|||0000-0002-6609-6119 Mas-Stachurska, Aleksandra|||0000-0003-4947-4111 Reixachs-Solé, Marina Pastor, Antoni|||0000-0003-3692-0696 Torre, Rafael de la|||0000-0002-6765-1866 Maldonado, Rafael|||0000-0002-4359-8773 Benito Villabriga, Begoña|||0000-0002-8668-1251 Eyras, Eduardo|||0000-0003-0793-6218 Rodríguez-Puertas, Rafael|||0000-0003-4517-5114 Campuzano, Victoria|||0000-0001-8128-2641 Ozaita, Andres|||0000-0002-2239-7403 |
| author |
Navarro-Romero, Alba |
| author_facet |
Navarro-Romero, Alba Galera-López, Lorena Ortiz-Romero, Paula|||0000-0002-6378-6763 Llorente-Ovejero, Alberto de los Reyes-Ramírez, Lucía Bengoetxea de Tena, Iker Garcia-Elias, Anna|||0000-0002-6609-6119 Mas-Stachurska, Aleksandra|||0000-0003-4947-4111 Reixachs-Solé, Marina Pastor, Antoni|||0000-0003-3692-0696 Torre, Rafael de la|||0000-0002-6765-1866 Maldonado, Rafael|||0000-0002-4359-8773 Benito Villabriga, Begoña|||0000-0002-8668-1251 Eyras, Eduardo|||0000-0003-0793-6218 Rodríguez-Puertas, Rafael|||0000-0003-4517-5114 Campuzano, Victoria|||0000-0001-8128-2641 Ozaita, Andres|||0000-0002-2239-7403 |
| author_role |
author |
| author2 |
Galera-López, Lorena Ortiz-Romero, Paula|||0000-0002-6378-6763 Llorente-Ovejero, Alberto de los Reyes-Ramírez, Lucía Bengoetxea de Tena, Iker Garcia-Elias, Anna|||0000-0002-6609-6119 Mas-Stachurska, Aleksandra|||0000-0003-4947-4111 Reixachs-Solé, Marina Pastor, Antoni|||0000-0003-3692-0696 Torre, Rafael de la|||0000-0002-6765-1866 Maldonado, Rafael|||0000-0002-4359-8773 Benito Villabriga, Begoña|||0000-0002-8668-1251 Eyras, Eduardo|||0000-0003-0793-6218 Rodríguez-Puertas, Rafael|||0000-0003-4517-5114 Campuzano, Victoria|||0000-0001-8128-2641 Ozaita, Andres|||0000-0002-2239-7403 |
| author2_role |
author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universitat Autònoma de Barcelona |
| dc.subject.none.fl_str_mv |
Williams-Beuren syndrome Intellectual disability Endocannabinoid system Cannabinoid type-1 receptor Mouse |
| topic |
Williams-Beuren syndrome Intellectual disability Endocannabinoid system Cannabinoid type-1 receptor Mouse |
| description |
Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor short-term object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with subchronic (10 days) JZL184, a selective inhibitor of monoacylglycerol lipase, specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiovascular function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS. Williams-Beuren syndrome (WBS) is a rare disorder that causes hyper-social behavior, intellectual disability, memory problems, and life-threatening overgrowth of the heart. Behavioral therapies can help improve the cognitive and social aspects of the syndrome and surgery is sometimes used to treat the effects on the heart, although often with limited success. However, there are currently no medications available to treat WBS. The endocannabinoid system - which consists of cannabis-like chemical messengers that bind to specific cannabinoid receptor proteins - has been shown to influence cognitive and social behaviors, as well as certain functions of the heart. This has led scientists to suspect that the endocannabinoid system may play a role in WBS, and drugs modifying this network of chemical messengers could help treat the rare condition. To investigate, Navarro-Romero, Galera-López et al. studied mice which had the same genetic deletion found in patients with WBS. Similar to humans, the male mice displayed hyper-social behaviors, had memory deficits and enlarged hearts. Navarro-Romero, Galera-López et al. found that these mutant mice also had differences in the function of the receptor protein cannabinoid type-1 (CB1). The genetically modified mice were then treated with an experimental drug called JZL184 that blocks the breakdown of endocannabinoids which bind to the CB1 receptor. This normalized the number and function of receptors in the brains of the WBS mice, and reduced their social and memory symptoms. The treatment also restored the animals' heart cells to a more normal size, improved the function of their heart tissue, and led to lower blood pressure. Further experiments revealed that the drug caused the mutant mice to activate many genes in their heart muscle cells to the same level as normal, healthy mice. These findings suggest that JZL184 or other drugs targeting the endocannabinoid system may help ease the symptoms associated with WBS. More studies are needed to test the drug's effectiveness in humans with this syndrome. Furthermore, the dramatic effect JZL184 has on the heart suggests that it might also help treat high blood pressure or conditions that cause the overgrowth of heart cells. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2 2022-01-01 2022 2022-01-01 |
| dc.type.none.fl_str_mv |
Article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://ddd.uab.cat/record/282415 https://dx.doi.org/urn:doi:10.7554/eLife.72560 |
| url |
https://ddd.uab.cat/record/282415 https://dx.doi.org/urn:doi:10.7554/eLife.72560 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.relation.none.fl_str_mv |
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 RTI2018-099282-B-I00 Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 SAF2017-84060-R Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI20/00153 Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 MDM-2014-0370 Ministerio de Educación, Cultura y Deporte https://doi.org/10.13039/501100003176 FPU13/01867 |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/ |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf |
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reponame:Dipòsit Digital de Documents de la UAB instname:Universitat Autònoma de Barcelona |
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Universitat Autònoma de Barcelona |
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Dipòsit Digital de Documents de la UAB |
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Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndromeNavarro-Romero, AlbaGalera-López, LorenaOrtiz-Romero, Paula|||0000-0002-6378-6763Llorente-Ovejero, Albertode los Reyes-Ramírez, LucíaBengoetxea de Tena, IkerGarcia-Elias, Anna|||0000-0002-6609-6119Mas-Stachurska, Aleksandra|||0000-0003-4947-4111Reixachs-Solé, MarinaPastor, Antoni|||0000-0003-3692-0696Torre, Rafael de la|||0000-0002-6765-1866Maldonado, Rafael|||0000-0002-4359-8773Benito Villabriga, Begoña|||0000-0002-8668-1251Eyras, Eduardo|||0000-0003-0793-6218Rodríguez-Puertas, Rafael|||0000-0003-4517-5114Campuzano, Victoria|||0000-0001-8128-2641Ozaita, Andres|||0000-0002-2239-7403Williams-Beuren syndromeIntellectual disabilityEndocannabinoid systemCannabinoid type-1 receptorMouseWilliams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor short-term object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with subchronic (10 days) JZL184, a selective inhibitor of monoacylglycerol lipase, specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiovascular function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS. Williams-Beuren syndrome (WBS) is a rare disorder that causes hyper-social behavior, intellectual disability, memory problems, and life-threatening overgrowth of the heart. Behavioral therapies can help improve the cognitive and social aspects of the syndrome and surgery is sometimes used to treat the effects on the heart, although often with limited success. However, there are currently no medications available to treat WBS. The endocannabinoid system - which consists of cannabis-like chemical messengers that bind to specific cannabinoid receptor proteins - has been shown to influence cognitive and social behaviors, as well as certain functions of the heart. This has led scientists to suspect that the endocannabinoid system may play a role in WBS, and drugs modifying this network of chemical messengers could help treat the rare condition. To investigate, Navarro-Romero, Galera-López et al. studied mice which had the same genetic deletion found in patients with WBS. Similar to humans, the male mice displayed hyper-social behaviors, had memory deficits and enlarged hearts. Navarro-Romero, Galera-López et al. found that these mutant mice also had differences in the function of the receptor protein cannabinoid type-1 (CB1). The genetically modified mice were then treated with an experimental drug called JZL184 that blocks the breakdown of endocannabinoids which bind to the CB1 receptor. This normalized the number and function of receptors in the brains of the WBS mice, and reduced their social and memory symptoms. The treatment also restored the animals' heart cells to a more normal size, improved the function of their heart tissue, and led to lower blood pressure. Further experiments revealed that the drug caused the mutant mice to activate many genes in their heart muscle cells to the same level as normal, healthy mice. These findings suggest that JZL184 or other drugs targeting the endocannabinoid system may help ease the symptoms associated with WBS. More studies are needed to test the drug's effectiveness in humans with this syndrome. Furthermore, the dramatic effect JZL184 has on the heart suggests that it might also help treat high blood pressure or conditions that cause the overgrowth of heart cells.Universitat Autònoma de Barcelona 22022-01-0120222022-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/282415https://dx.doi.org/urn:doi:10.7554/eLife.72560reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 RTI2018-099282-B-I00Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 SAF2017-84060-RInstituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI20/00153Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 MDM-2014-0370Ministerio de Educación, Cultura y Deporte https://doi.org/10.13039/501100003176 FPU13/01867open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2824152026-06-06T12:50:31Z |
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15.301603 |