Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington’s disease

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dc.contributor.authorBlázquez Ortiz, Cristina
dc.contributor.authorChiarlone, Anna
dc.contributor.authorSagredo Ezquioga, Onintza
dc.contributor.authorAguado Sánchez, Tania
dc.contributor.authorPazos, M. Ruth
dc.contributor.authorResel, Eva
dc.contributor.authorPalazuelos Diego, Javier
dc.contributor.authorJulien, Boris
dc.contributor.authorSalazar, María
dc.contributor.authorBörner, Christine
dc.contributor.authorBenito, Cristina
dc.contributor.authorCarrasco, Carolina
dc.contributor.authorDiez Zaera, María
dc.contributor.authorPaoletti, Paola
dc.contributor.authorDíaz Hernández, Miguel
dc.contributor.authorRuiz, Carolina
dc.contributor.authorSendtner, Michael
dc.contributor.authorLucas, José J.
dc.contributor.authorGarcía de Yébenes, Justo
dc.contributor.authorMarsicano, Giovanni
dc.contributor.authorMonory, Krisztina
dc.contributor.authorLutz, Beat
dc.contributor.authorRomero, Julián
dc.contributor.authorAlberch, Jordi
dc.contributor.authorGinés, Silvia
dc.contributor.authorKraus, Jürgen
dc.contributor.authorFernández Ruiz, José Javier
dc.contributor.authorGalve Roperh, Ismael
dc.contributor.authorGuzmán Pastor, Manuel
dc.date.accessioned2023-12-19T19:33:48Z
dc.date.available2023-12-19T19:33:48Z
dc.date.issued2010-10-07
dc.description.abstractEndocannabinoids act as neuromodulatory and neuroprotective cues by engaging type 1 cannabinoid receptors. These receptors are highly abundant in the basal ganglia and play a pivotal role in the control of motor behaviour. An early downregulation of type 1 cannabinoid receptors has been documented in the basal ganglia of patients with Huntington’s disease and animal models. However, the pathophysiological impact of this loss of receptors in Huntington’s disease is as yet unknown. Here, we generated a double-mutant mouse model that expresses human mutant huntingtin exon 1 in a type 1 cannabinoid receptor-null background, and found that receptor deletion aggravates the symptoms, neuropathology and molecular pathology of the disease. Moreover, pharmacological administration of the cannabinoid Δ9-tetrahydrocannabinol to mice expressing human mutant huntingtin exon 1 exerted a therapeutic effect and ameliorated those parameters. Experiments conducted in striatal cells show that the mutant huntingtin-dependent downregulation of the receptors involves the control of the type 1 cannabinoid receptor gene promoter by repressor element 1 silencing transcription factor and sensitizes cells to excitotoxic damage. We also provide in vitro and in vivo evidence that supports type 1 cannabinoid receptor control of striatal brain-derived neurotrophic factor expression and the decrease in brain-derived neurotrophic factor levels concomitant with type 1 cannabinoid receptor loss, which may contribute significantly to striatal damage in Huntington’s disease. Altogether, these results support the notion that downregulation of type 1 cannabinoid receptors is a key pathogenic event in Huntington’s disease, and suggest that activation of these receptors in patients with Huntington’s disease may attenuate disease progression.
dc.description.departmentDepto. de Bioquímica y Biología Molecular
dc.description.facultyFac. de Ciencias Biológicas
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Ciencia e Innovación (MICINN)
dc.description.sponsorshipComunidad de Madrid-Universidad Complutense de Madrid
dc.description.sponsorshipGerman Bundesministerium für Bildung und Forschung
dc.description.statuspub
dc.identifier.doi10.1093/brain/awq278
dc.identifier.essn1460-2156
dc.identifier.issn0006-8950
dc.identifier.officialurlhttps://academic.oup.com/brain/article/134/1/119/291068
dc.identifier.urihttps://hdl.handle.net/20.500.14352/91567
dc.issue.number1
dc.journal.titleBrain
dc.language.isoeng
dc.page.final136
dc.page.initial119
dc.publisherOxford University Press
dc.relation.projectID(SAF2009-08403 , SAF2009-11847, SAF2007-61565)
dc.relation.projectID(SAL2006/261, 950344)
dc.relation.projectID01ZZ0407
dc.rights.accessRightsrestricted access
dc.subject.cdu577.1
dc.subject.cdu577.2
dc.subject.cdu612.8
dc.subject.keywordCannabinoid
dc.subject.keywordReceptor
dc.subject.keywordHuntington’s disease
dc.subject.keywordNeuroprotection
dc.subject.keywordExperimental therapeutics
dc.subject.ucmBiología molecular (Biología)
dc.subject.ucmBioquímica (Biología)
dc.subject.ucmNeurociencias (Medicina)
dc.subject.unesco2403 Bioquímica
dc.subject.unesco2415 Biología Molecular
dc.subject.unesco2490 Neurociencias
dc.titleLoss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington’s disease
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number134
dspace.entity.typePublication
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