Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3.
Main Author: | |
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Publication Date: | 2016 |
Other Authors: | , , , , , , , , |
Format: | Article |
Language: | eng |
Source: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Download full: | http://hdl.handle.net/1822/45034 |
Summary: | Spinocerebellar ataxia type-3 (SCA-3) is a rare disease but it is the most frequent type within the autosomal dominant inherited ataxias. The disease lacks an effective treatment to alleviate major symptoms and to modify disease progression. Our recent findings that endocannabinoid receptors and enzymes are significantly altered in the post-mortem cerebellum of patients affected by autosomal-dominant hereditary ataxias suggest that targeting the endocannabinoid signaling system may be a promising therapeutic option. Our goal was to investigate the status of the endocannabinoid signaling system in a transgenic mouse model of SCA-3, in the two CNS structures most affected in this disease cerebellum and brainstem. These animals exhibited progressive motor incoordination, imbalance, abnormal gait, muscle weakness, and dystonia, in parallel to reduced in vivo brain glucose metabolism, deterioration of specific neuron subsets located in the dentate nucleus and pontine nuclei, small changes in microglial morphology, and reduction in glial glutamate transporters. Concerning the endocannabinoid signaling, our data indicated no changes in CB2 receptors. By contrast, CB1 receptors increased in the Purkinje cell layer, in particular in terminals of basket cells, but they were reduced in the dentate nucleus. We also measured the levels of endocannabinoid lipids and found reductions in anandamide and oleoylethanolamide in the brainstem. These changes correlated with an increase in the FAAH enzyme in the brainstem, which also occurred in some cerebellar areas, whereas other endocannabinoid-related enzymes were not altered. Collectively, our results in SCA-3 mutant mice confirm a possible dysregulation in the endocannabinoid system in the most important brain structures affected in this type of ataxia, suggesting that a pharmacological manipulation addressed to correct these changes could be a promising option in SCA-3. |
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Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3.CannabinoidsEndocannabinoid signaling systemAutosomal-dominant inherited ataxiasSpinocerebellar ataxia-3Machado-Joseph diseaseMotor incoordinationCiências Médicas::Ciências da SaúdeScience & TechnologySpinocerebellar ataxia type-3 (SCA-3) is a rare disease but it is the most frequent type within the autosomal dominant inherited ataxias. The disease lacks an effective treatment to alleviate major symptoms and to modify disease progression. Our recent findings that endocannabinoid receptors and enzymes are significantly altered in the post-mortem cerebellum of patients affected by autosomal-dominant hereditary ataxias suggest that targeting the endocannabinoid signaling system may be a promising therapeutic option. Our goal was to investigate the status of the endocannabinoid signaling system in a transgenic mouse model of SCA-3, in the two CNS structures most affected in this disease cerebellum and brainstem. These animals exhibited progressive motor incoordination, imbalance, abnormal gait, muscle weakness, and dystonia, in parallel to reduced in vivo brain glucose metabolism, deterioration of specific neuron subsets located in the dentate nucleus and pontine nuclei, small changes in microglial morphology, and reduction in glial glutamate transporters. Concerning the endocannabinoid signaling, our data indicated no changes in CB2 receptors. By contrast, CB1 receptors increased in the Purkinje cell layer, in particular in terminals of basket cells, but they were reduced in the dentate nucleus. We also measured the levels of endocannabinoid lipids and found reductions in anandamide and oleoylethanolamide in the brainstem. These changes correlated with an increase in the FAAH enzyme in the brainstem, which also occurred in some cerebellar areas, whereas other endocannabinoid-related enzymes were not altered. Collectively, our results in SCA-3 mutant mice confirm a possible dysregulation in the endocannabinoid system in the most important brain structures affected in this type of ataxia, suggesting that a pharmacological manipulation addressed to correct these changes could be a promising option in SCA-3.This study has been supported by MICINN (SAF2009-11847 and SAF2015-68580-C2-1-R), CIBERNED (CB06/05/0089), "Fundacion Eugenio Rodriguez Pascual" and the Research and Education Component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin. Carmen Rodriguez-Cueto was a predoctoral fellow supported by FPI Program-Ministry of Science. Authors are indebted to Yolanda Garcia-Movellan for administrative support.ElsevierUniversidade do MinhoMaciel, P.Rodríguez-Cueto, CarmenHernández-Gálvez, MariluzHillard, Cecília J.García-García, LuísValdeolivas, SaraPozo, Miguel A.Ramos, José A.Gómez-Ruiz, MariaFernández-Ruiz, Javier2016-01-052016-01-05T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/45034engRodríguez-Cueto, C., Hernández-Gálvez, M., Hillard, C. J., Maciel, P., García-García, L., Valdeolivas, S., . . . Fernández-Ruiz, J. (2016). Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3. [Article]. Neuroscience, 339, 191-209. doi: 10.1016/j.neuroscience.2016.09.0460306-452210.1016/j.neuroscience.2016.09.04627717809http://www.journals.elsevier.cominfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:37:29Zoai:repositorium.sdum.uminho.pt:1822/45034Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:33:47.631526Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3. |
title |
Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3. |
spellingShingle |
Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3. Maciel, P. Cannabinoids Endocannabinoid signaling system Autosomal-dominant inherited ataxias Spinocerebellar ataxia-3 Machado-Joseph disease Motor incoordination Ciências Médicas::Ciências da Saúde Science & Technology |
title_short |
Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3. |
title_full |
Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3. |
title_fullStr |
Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3. |
title_full_unstemmed |
Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3. |
title_sort |
Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3. |
author |
Maciel, P. |
author_facet |
Maciel, P. Rodríguez-Cueto, Carmen Hernández-Gálvez, Mariluz Hillard, Cecília J. García-García, Luís Valdeolivas, Sara Pozo, Miguel A. Ramos, José A. Gómez-Ruiz, Maria Fernández-Ruiz, Javier |
author_role |
author |
author2 |
Rodríguez-Cueto, Carmen Hernández-Gálvez, Mariluz Hillard, Cecília J. García-García, Luís Valdeolivas, Sara Pozo, Miguel A. Ramos, José A. Gómez-Ruiz, Maria Fernández-Ruiz, Javier |
author2_role |
author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Maciel, P. Rodríguez-Cueto, Carmen Hernández-Gálvez, Mariluz Hillard, Cecília J. García-García, Luís Valdeolivas, Sara Pozo, Miguel A. Ramos, José A. Gómez-Ruiz, Maria Fernández-Ruiz, Javier |
dc.subject.por.fl_str_mv |
Cannabinoids Endocannabinoid signaling system Autosomal-dominant inherited ataxias Spinocerebellar ataxia-3 Machado-Joseph disease Motor incoordination Ciências Médicas::Ciências da Saúde Science & Technology |
topic |
Cannabinoids Endocannabinoid signaling system Autosomal-dominant inherited ataxias Spinocerebellar ataxia-3 Machado-Joseph disease Motor incoordination Ciências Médicas::Ciências da Saúde Science & Technology |
description |
Spinocerebellar ataxia type-3 (SCA-3) is a rare disease but it is the most frequent type within the autosomal dominant inherited ataxias. The disease lacks an effective treatment to alleviate major symptoms and to modify disease progression. Our recent findings that endocannabinoid receptors and enzymes are significantly altered in the post-mortem cerebellum of patients affected by autosomal-dominant hereditary ataxias suggest that targeting the endocannabinoid signaling system may be a promising therapeutic option. Our goal was to investigate the status of the endocannabinoid signaling system in a transgenic mouse model of SCA-3, in the two CNS structures most affected in this disease cerebellum and brainstem. These animals exhibited progressive motor incoordination, imbalance, abnormal gait, muscle weakness, and dystonia, in parallel to reduced in vivo brain glucose metabolism, deterioration of specific neuron subsets located in the dentate nucleus and pontine nuclei, small changes in microglial morphology, and reduction in glial glutamate transporters. Concerning the endocannabinoid signaling, our data indicated no changes in CB2 receptors. By contrast, CB1 receptors increased in the Purkinje cell layer, in particular in terminals of basket cells, but they were reduced in the dentate nucleus. We also measured the levels of endocannabinoid lipids and found reductions in anandamide and oleoylethanolamide in the brainstem. These changes correlated with an increase in the FAAH enzyme in the brainstem, which also occurred in some cerebellar areas, whereas other endocannabinoid-related enzymes were not altered. Collectively, our results in SCA-3 mutant mice confirm a possible dysregulation in the endocannabinoid system in the most important brain structures affected in this type of ataxia, suggesting that a pharmacological manipulation addressed to correct these changes could be a promising option in SCA-3. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-01-05 2016-01-05T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/45034 |
url |
http://hdl.handle.net/1822/45034 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Rodríguez-Cueto, C., Hernández-Gálvez, M., Hillard, C. J., Maciel, P., García-García, L., Valdeolivas, S., . . . Fernández-Ruiz, J. (2016). Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3. [Article]. Neuroscience, 339, 191-209. doi: 10.1016/j.neuroscience.2016.09.046 0306-4522 10.1016/j.neuroscience.2016.09.046 27717809 http://www.journals.elsevier.com |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
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openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Elsevier |
publisher.none.fl_str_mv |
Elsevier |
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