RT Journal Article
T1 Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington’s disease
A1 Blázquez Ortiz, Cristina
A1 Chiarlone, Anna
A1 Sagredo Ezquioga, Onintza
A1 Aguado Sánchez, Tania
A1 Pazos, M. Ruth
A1 Resel, Eva
A1 Palazuelos Diego, Javier
A1 Julien, Boris
A1 Salazar, María
A1 Börner, Christine
A1 Benito, Cristina
A1 Carrasco, Carolina
A1 Diez Zaera, María
A1 Paoletti, Paola
A1 Díaz Hernández, Miguel
A1 Ruiz, Carolina
A1 Sendtner, Michael
A1 Lucas, José J.
A1 García de Yébenes, Justo
A1 Marsicano, Giovanni
A1 Monory, Krisztina
A1 Lutz, Beat
A1 Romero, Julián
A1 Alberch, Jordi
A1 Ginés, Silvia
A1 Kraus, Jürgen
A1 Fernández Ruiz, José Javier
A1 Galve Roperh, Ismael
A1 Guzmán Pastor, Manuel
AB Endocannabinoids 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.
PB Oxford University Press
SN 0006-8950
YR 2010
FD 2010-10-07
LK https://hdl.handle.net/20.500.14352/91567
UL https://hdl.handle.net/20.500.14352/91567
LA eng
NO Ministerio de Ciencia e Innovación (MICINN)
NO Comunidad de Madrid-Universidad Complutense de Madrid
NO German Bundesministerium für Bildung und Forschung
DS Docta Complutense
RD 1 sept 2024