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Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington's disease.
Brain. 2011 Jan; 134(Pt 1):119-36.B

Abstract

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 Δ(9)-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.

Authors+Show Affiliations

Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Huntington’s Disease and Ataxias Collaborative Project, 28040 Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20929960

Citation

Blázquez, Cristina, et al. "Loss of Striatal Type 1 Cannabinoid Receptors Is a Key Pathogenic Factor in Huntington's Disease." Brain : a Journal of Neurology, vol. 134, no. Pt 1, 2011, pp. 119-36.
Blázquez C, Chiarlone A, Sagredo O, et al. Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington's disease. Brain. 2011;134(Pt 1):119-36.
Blázquez, C., Chiarlone, A., Sagredo, O., Aguado, T., Pazos, M. R., Resel, E., Palazuelos, J., Julien, B., Salazar, M., Börner, C., Benito, C., Carrasco, C., Diez-Zaera, M., Paoletti, P., Díaz-Hernández, M., Ruiz, C., Sendtner, M., Lucas, J. J., de Yébenes, J. G., ... Guzmán, M. (2011). Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington's disease. Brain : a Journal of Neurology, 134(Pt 1), 119-36. https://doi.org/10.1093/brain/awq278
Blázquez C, et al. Loss of Striatal Type 1 Cannabinoid Receptors Is a Key Pathogenic Factor in Huntington's Disease. Brain. 2011;134(Pt 1):119-36. PubMed PMID: 20929960.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington's disease. AU - Blázquez,Cristina, AU - Chiarlone,Anna, AU - Sagredo,Onintza, AU - Aguado,Tania, AU - Pazos,M Ruth, AU - Resel,Eva, AU - Palazuelos,Javier, AU - Julien,Boris, AU - Salazar,María, AU - Börner,Christine, AU - Benito,Cristina, AU - Carrasco,Carolina, AU - Diez-Zaera,María, AU - Paoletti,Paola, AU - Díaz-Hernández,Miguel, AU - Ruiz,Carolina, AU - Sendtner,Michael, AU - Lucas,José J, AU - de Yébenes,Justo G, AU - Marsicano,Giovanni, AU - Monory,Krisztina, AU - Lutz,Beat, AU - Romero,Julián, AU - Alberch,Jordi, AU - Ginés,Silvia, AU - Kraus,Jürgen, AU - Fernández-Ruiz,Javier, AU - Galve-Roperh,Ismael, AU - Guzmán,Manuel, Y1 - 2010/10/07/ PY - 2010/10/9/entrez PY - 2010/10/12/pubmed PY - 2011/1/22/medline SP - 119 EP - 36 JF - Brain : a journal of neurology JO - Brain VL - 134 IS - Pt 1 N2 - 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 Δ(9)-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. SN - 1460-2156 UR - https://www.unboundmedicine.com/medline/citation/20929960/Loss_of_striatal_type_1_cannabinoid_receptors_is_a_key_pathogenic_factor_in_Huntington's_disease_ L2 - https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awq278 DB - PRIME DP - Unbound Medicine ER -