Varani K, Bachoud-Lévi A-C, Mariotti C, Tarditi A, Abbracchio M P, Gasperi V, Borea P A, Dolbeau G, Gellera C, Solari A, Rosser A, Naji J, Handley O, Maccarrone M, Peschanski Marc, DiDonato S, Cattaneo E
Department of Clinical and Experimental Medicine, Pharmacology Unit, University of Ferrara, Italy.
Neurobiol Dis. 2007 Jul;27(1):36-43. doi: 10.1016/j.nbd.2007.03.011. Epub 2007 Apr 5.
Huntington's disease is one of a group of hereditary neurodegenerative diseases characterized by a glutamine expansion (polyQ) in proteins which are expressed in various cell populations. In agreement with this widespread distribution, we have previously shown that A(2A) receptor signaling is affected in mouse brain as well as in peripheral blood cells from a small cohort of HD patients. Here we analyzed a total of 252 subjects, including 126 HD gene-positive individuals, from different clinical sites. Consistent with our previous data we show that A(2A) receptor B(max) values are robustly increased at all HD stages as well as in 32 pre-symptomatic subjects. We report that the same abnormality is present also in other polyQ but not in non-polyQ inherited neurological disorders. Finally, we demonstrate that the same peripheral cells exhibit an altered membrane fluidity, a finding that may explain the observed change in receptor density. We argue that the observed alteration in lymphocytes reflects the presence of the mutant protein, and we suggest that the measure of the A(2A) receptor binding activity might be of potential interest for a peripheral assessment of chemicals capable of interfering with the immediate toxic effects of the mutation.
亨廷顿舞蹈症是一组遗传性神经退行性疾病之一，其特征是在各种细胞群体中表达的蛋白质中存在谷氨酰胺扩增（polyQ）。与这种广泛分布一致，我们之前已经表明，A(2A)受体信号传导在小鼠大脑以及一小群HD患者的外周血细胞中受到影响。在这里，我们分析了来自不同临床地点的总共252名受试者，包括126名HD基因阳性个体。与我们之前的数据一致，我们表明，在HD的所有阶段以及32名症状前受试者中，A(2A)受体的B(max)值均显著增加。我们报告称，在其他polyQ遗传性神经疾病中也存在相同的异常，但在非polyQ遗传性神经疾病中则不存在。最后，我们证明相同的外周细胞表现出膜流动性改变，这一发现可能解释了观察到的受体密度变化。我们认为，在淋巴细胞中观察到的改变反映了突变蛋白的存在，并且我们建议，A(2A)受体结合活性的测量对于能够干扰突变直接毒性作用的化学物质的外周评估可能具有潜在意义。
