RT Journal Article
T1 Astroglial monoacylglycerol lipase controls mutant huntingtin-induced damage of striatal neurons
A1 Ruiz Calvo, Andrea
A1 Bajo Grañeras, Raquel
A1 Maroto Martínez, Irene Berenice
A1 Zian, Debora
A1 Grabner, Gernot F.
A1 García-Taboada, Elena
A1 Resel, Eva
A1 Zechner, Rudolf
A1 Zimmermann, Robert
A1 Ortega Gutiérrez, Silvia
A1 Galve Roperh, Ismael
A1 Bellocchio, Luigi
A1 Guzmán, Manuel
AB Cannabinoids 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.
PB Elsevier
SN 0028-3908
YR 2019
FD 2019-05-15
LK https://hdl.handle.net/20.500.14352/12334
UL https://hdl.handle.net/20.500.14352/12334
LA eng
NO Ministerio de Ciencia e Innovación (MICINN)/FEDER
DS Docta Complutense
RD 13 abr 2025