Astroglial monoacylglycerol lipase controls mutant huntingtin-induced damage of striatal neurons

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dc.contributor.authorRuiz Calvo, Andrea
dc.contributor.authorBajo Grañeras, Raquel
dc.contributor.authorMaroto, Irene B.
dc.contributor.authorZian, Debora
dc.contributor.authorGrabner, Gernot F.
dc.contributor.authorGarcía-Taboada, Elena
dc.contributor.authorResel, Eva
dc.contributor.authorZechner, Rudolf
dc.contributor.authorZimmermann, Robert
dc.contributor.authorOrtega-Gutiérrez, Silvia
dc.contributor.authorGalve Roperh, Ismael
dc.contributor.authorBellocchio, Luigi
dc.contributor.authorGuzmán, Manuel
dc.date.accessioned2023-06-17T12:30:32Z
dc.date.available2023-06-17T12:30:32Z
dc.date.issued2019-05-15
dc.description.abstractCannabinoids exert neuroprotection in a wide array of preclinical models. A number of these studies has focused on cannabinoid CB1 receptors in striatal medium spiny neurons (MSNs) and the most characteristic MSN-degenerative disease, Huntington's disease (HD). Accruing evidence supports that astrocytes contribute to drive HD progression, and that they express CB1 receptors, degrade endocannabinoids, and modulate endocannabinergic transmission. However, the possible role of the astroglial endocannabinoid system in controlling MSN integrity remains unknown. Here, we show that JZL-184, a selective inhibitor of monoacylglycerol lipase (MGL), the key enzyme that deactivates the endocannabinoid 2-arachidonoylglycerol, prevented the mutant huntingtin-induced up-regulation of the pro-inflammatory cytokine tumor necrosis factor-α in primary mouse striatal astrocytes via CB1 receptors. To study the role of astroglial MGL in vivo, we injected stereotactically into the mouse dorsal striatum viral vectors that encode mutant or normal huntingtin under the control of the glial fibrillary acidic protein promoter. We observed that, in wild-type mice, pharmacological blockade of MGL with JZL-184 (8 mg/kg/day, i.p.) conferred neuroprotection against mutant huntingtin-induced striatal damage, as evidenced by the prevention of MSN loss, astrogliosis, and motor coordination impairment. We next found that conditional mutant mice bearing a genetic deletion of MGL selectively in astroglial cells (MGLfloxed/floxed;GFAP-Cre/+ mice) were resistant to mutant huntingtin-induced MSN loss, astrogliosis, and motor coordination impairment. Taken together, these data support that astroglial MGL controls the availability of a 2-arachidonoylglycerol pool that ensues protection of MSNs in the mouse striatum in vivo, thus providing a potential druggable target for reducing striatal neurodegeneration.
dc.description.departmentSección Deptal. de Bioquímica y Biología Molecular (Biológicas)
dc.description.facultyFac. de Ciencias Biológicas
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Ciencia e Innovación (MICINN)/FEDER
dc.description.statuspub
dc.eprint.idhttps://eprints.ucm.es/id/eprint/60652
dc.identifier.doihttps://doi-org.bucm.idm.oclc.org/10.1016/j.neuropharm.2019.03.027
dc.identifier.issn0028-3908
dc.identifier.officialurlhttps://www-sciencedirect-com.bucm.idm.oclc.org/science/article/pii/S0028390819301066#!
dc.identifier.urihttps://hdl.handle.net/20.500.14352/12334
dc.journal.titleNeuropharmacology
dc.language.isoeng
dc.page.final144
dc.page.initial134
dc.publisherElsevier
dc.relation.projectID(SAF2015-64945-R; SAF2016-78792-R)
dc.rights.accessRightsrestricted access
dc.subject.cdu577.1
dc.subject.cdu577.2
dc.subject.cdu612.8
dc.subject.keywordAstrocyte
dc.subject.keywordCannabinoid receptor
dc.subject.keywordEndocannabinoid
dc.subject.keywordMedium spiny neuron
dc.subject.keywordMonoacylglycerol lipase
dc.subject.keywordNeuroprotection
dc.subject.ucmBiología molecular (Biología)
dc.subject.ucmBioquímica (Biología)
dc.subject.ucmNeurociencias (Biológicas)
dc.subject.unesco2415 Biología Molecular
dc.subject.unesco2302 Bioquímica
dc.subject.unesco2490 Neurociencias
dc.titleAstroglial monoacylglycerol lipase controls mutant huntingtin-induced damage of striatal neurons
dc.typejournal article
dc.volume.number150
dspace.entity.typePublication
relation.isAuthorOfPublication5795a7c4-d0fd-45f4-a94f-c721af6fe686
relation.isAuthorOfPublication8c2a1d13-f2a3-4355-8b66-73e0f97c0cea
relation.isAuthorOfPublication.latestForDiscovery8c2a1d13-f2a3-4355-8b66-73e0f97c0cea
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