Rodríguez-Cueto Carmen, Hernández-Gálvez Mariluz, Hillard Cecilia J, Maciel Patricia, García-García Luis, Valdeolivas Sara, Pozo Miguel A, Ramos José A, Gómez-Ruiz María, Fernández-Ruiz Javier
Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain; Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense, Madrid, Spain.
Neuroscience. 2016 Dec 17;339:191-209. doi: 10.1016/j.neuroscience.2016.09.046. Epub 2016 Oct 4.
Spinocerebellar ataxia type-3 (SCA-3) is a rare disease but it is the most frequent type within the autosomal dominant inherited ataxias. The disease lacks an effective treatment to alleviate major symptoms and to modify disease progression. Our recent findings that endocannabinoid receptors and enzymes are significantly altered in the post-mortem cerebellum of patients affected by autosomal-dominant hereditary ataxias suggest that targeting the endocannabinoid signaling system may be a promising therapeutic option. Our goal was to investigate the status of the endocannabinoid signaling system in a transgenic mouse model of SCA-3, in the two CNS structures most affected in this disease - cerebellum and brainstem. These animals exhibited progressive motor incoordination, imbalance, abnormal gait, muscle weakness, and dystonia, in parallel to reduced in vivo brain glucose metabolism, deterioration of specific neuron subsets located in the dentate nucleus and pontine nuclei, small changes in microglial morphology, and reduction in glial glutamate transporters. Concerning the endocannabinoid signaling, our data indicated no changes in CB receptors. By contrast, CB receptors increased in the Purkinje cell layer, in particular in terminals of basket cells, but they were reduced in the dentate nucleus. We also measured the levels of endocannabinoid lipids and found reductions in anandamide and oleoylethanolamide in the brainstem. These changes correlated with an increase in the FAAH enzyme in the brainstem, which also occurred in some cerebellar areas, whereas other endocannabinoid-related enzymes were not altered. Collectively, our results in SCA-3 mutant mice confirm a possible dysregulation in the endocannabinoid system in the most important brain structures affected in this type of ataxia, suggesting that a pharmacological manipulation addressed to correct these changes could be a promising option in SCA-3.
3型脊髓小脑共济失调（SCA-3）是一种罕见疾病，但却是常染色体显性遗传性共济失调中最常见的类型。该疾病缺乏缓解主要症状和改变疾病进展的有效治疗方法。我们最近的研究发现，在常染色体显性遗传性共济失调患者的死后小脑中，内源性大麻素受体和酶发生了显著改变，这表明靶向内源性大麻素信号系统可能是一种有前景的治疗选择。我们的目标是研究SCA-3转基因小鼠模型中内源性大麻素信号系统的状态，该模型中受这种疾病影响最严重的两个中枢神经系统结构是小脑和脑干。这些动物表现出进行性运动不协调、失衡、异常步态、肌肉无力和肌张力障碍，同时伴有体内脑葡萄糖代谢降低、齿状核和脑桥核中特定神经元亚群的退化、小胶质细胞形态的微小变化以及胶质谷氨酸转运体的减少。关于内源性大麻素信号，我们的数据表明CB受体没有变化。相比之下，CB受体在浦肯野细胞层增加，特别是在篮状细胞的终末，但在齿状核中减少。我们还测量了内源性大麻素脂质的水平，发现脑干中花生四烯酸乙醇胺和油酰乙醇胺减少。这些变化与脑干中脂肪酸酰胺水解酶（FAAH）的增加相关，在一些小脑区域也出现了这种情况，而其他与内源性大麻素相关的酶没有改变。总体而言，我们在SCA-3突变小鼠中的结果证实了在这种共济失调类型中受影响最重要的脑结构内源性大麻素系统可能存在失调，这表明针对纠正这些变化的药物操作可能是SCA-3中有前景的选择。
