Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Huntington’s Disease and Ataxias Collaborative Project, 28040 Madrid, Spain.
Brain. 2011 Jan;134(Pt 1):119-36. doi: 10.1093/brain/awq278. Epub 2010 Oct 7.
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.
内源性大麻素通过与 1 型大麻素受体结合发挥神经调质和神经保护作用。这些受体在基底神经节中高度丰富，在控制运动行为方面发挥着关键作用。在亨廷顿病患者和动物模型的基底神经节中，已经记录到 1 型大麻素受体的早期下调。然而，这种受体丢失在亨廷顿病中的病理生理影响尚不清楚。在这里，我们生成了一种双突变小鼠模型，该模型在 1 型大麻素受体缺失背景下表达人类突变亨廷顿外显子 1，并发现受体缺失加重了疾病的症状、神经病理学和分子病理学。此外，向表达人类突变亨廷顿外显子 1 的小鼠给予大麻素 Δ(9)-四氢大麻酚进行药理学处理发挥了治疗作用，并改善了这些参数。在纹状体细胞中进行的实验表明，突变亨廷顿依赖性受体下调涉及 1 型大麻素受体基因启动子的抑制元件 1 沉默转录因子的控制，并使细胞对兴奋性毒性损伤敏感。我们还提供了体外和体内证据，支持 1 型大麻素受体控制纹状体脑源性神经营养因子的表达，以及与 1 型大麻素受体丢失同时发生的脑源性神经营养因子水平降低，这可能对亨廷顿病中的纹状体损伤有重要贡献。总之，这些结果支持了 1 型大麻素受体下调是亨廷顿病的关键致病事件的观点，并表明在亨廷顿病患者中激活这些受体可能会减轻疾病进展。
