Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington’s disease.

Cristina Blázquez, Anna Chiarlone, Onintza Sagredo, Tania Aguado, M. Ruth Pazos, Eva Resel, Javier Palazuelos, Boris Julien, María Salazar, Christine Börner, Cristina Benito, Carolina Carrasco, María Diez-Zaera, Paola Paoletti, Miguel Díaz-Hernández, Carolina Ruiz, Michael Sendtner, José J. Lucas, Justo G. de Yébenes, Giovanni Marsicano, Krisztina Monory, Beat Lutz, Julián Romero, Jordi Alberch, Silvia Ginés, Jürgen Kraus, Javier Fernández-Ruiz, Ismael Galve-Roperh, Manuel Guzmán
Brain. 2010-10-07; 134(1): 119-136
DOI: 10.1093/brain/awq278

Lire sur PubMed

1. Brain. 2011 Jan;134(Pt 1):119-36. doi: 10.1093/brain/awq278. Epub 2010 Oct 7.

Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in
Huntington’s disease.

Blázquez C(1), Chiarlone A, Sagredo O, Aguado T, Pazos MR, 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 JJ, de Yébenes JG, Marsicano G,
Monory K, Lutz B, Romero J, Alberch J, Ginés S, Kraus J, Fernández-Ruiz J,
Galve-Roperh I, Guzmán M.

Author information:
(1)Centro de Investigación Biomédica en Red sobre Enfermedades
Neurodegenerativas, Huntington’s Disease and Ataxias Collaborative Project, 28040
Madrid, Spain.

Comment in
Brain. 2011 Nov;134(Pt 11):e191; author reply e192.

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.

DOI: 10.1093/brain/awq278
PMID: 20929960 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus