Blázquez Ortiz, CristinaChiarlone, AnnaSagredo Ezquioga, OnintzaAguado Sánchez, TaniaPazos, RuthResel, EvaPalazuelos Diego, JavierJulien, BorisSalazar, MaríaBörner, ChristineBenito, CristinaCarrasco, CarolinaDiez Zaera, MaríaPaoletti, PaolaDíaz Hernández, MiguelRuiz, CarolinaSendtner, MichaelLucas, JoséGarcía de Yébenes, JustoMarsicano, GiovanniMonory, KrisztinaLutz, BeatRomero, JuliánAlberch, JordiGinés, SilviaKraus, JürgenFernández Ruiz, José JavierGalve Roperh, IsmaelGuzmán Pastor, Manuel2023-12-192023-12-192010Blázquez, Cristina, et al. «Loss of Striatal Type 1 Cannabinoid Receptors Is a Key Pathogenic Factor in Huntington’s Disease». Brain, vol. 134, n.o 1, enero de 2011, pp. 119-36. https://doi.org/10.1093/brain/awq278.0006-895010.1093/brain/awq278https://hdl.handle.net/20.500.14352/91567Endocannabinoids 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.engjournal article1460-2156https://doi.org/10.1093/brain/awq278restricted access577.1577.2612.8CannabinoidReceptorHuntington’s diseaseNeuroprotectionExperimental therapeuticsBiología molecular (Biología)Bioquímica (Biología)Neurociencias (Medicina)2403 Bioquímica2415 Biología Molecular2490 Neurociencias