Severe deficiency of the fatty acid amide hydrolase (FAAH) activity segregates with the Huntington's disease mutation in peripheral lymphocytes
Severe deficiency of the fatty acid amide hydrolase (FAAH) activity segregates with the Huntington's disease mutation in peripheral lymphocytes
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DOI：
10.1016/j.nbd.2007.04.012
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发表时间：
2007-07-01
影响因子：
6.1
通讯作者：
Maccarrone, Mauro
中科院分区：
文献类型：
--
作者：
Battista, Natalia;Bari, Monica;Maccarrone, Mauro
寻找神经退行性疾病的外周标记物的目的是识别有助于监测未来治疗方法在易于接近的细胞中的效果的分子。在这里，我们重点关注内源性大麻素系统在亨廷顿病 (HD) 中的参与。我们检测了 HD 患者和健康对照者的外周淋巴细胞，发现与健康受试者相比，HD 患者的脂肪酸酰胺水解酶 (FAAH)（一种降解内源性大麻素大麻素 (AEA) 的酶）活性显着降低（降至不到 10%）。与此同时，HD 中 AEA 的内源水平比健康淋巴细胞高出 6 倍，而内源性大麻素系统的其他元素不受 HD 影响。 HD淋巴细胞中的低FAAR活性并不是由于蛋白质表达下调，而是由于胞质和不可逆抑制剂阻断了酶活性。最后，HD 前期患者的 FAAH 活性存在缺陷，HD 患者的大脑与健康对照组相比也是如此。总而言之，我们的数据表明淋巴细胞中的 FAAH 活性反映了大脑中发生的一些代谢变化，它是一种可测量的非遗传外周标记，与 HD 突变分离，并且它可能作为测试对突变蛋白的广泛毒性作用具有活性的化学物质的目标。 (c) 2007 Elsevier Inc. 保留所有权利。
The search for peripheral markers of neurodegenerative diseases aims at identifying molecules that could help in monitoring the effects of future therapeutics in easily accessible cells. Here we focused on the involvement of the endocannabinoid system in Huntington's disease (HD). We assayed peripheral lymphocytes from HD patients and healthy controls, and found that the activity of the fatty acid amide hydrolase (FAAH), the enzyme that degrades the endocannabinoid anandamide (AEA), was dramatically decreased (down to less than 10%) in HD compared to healthy subjects. Concomitantly, the endogenous levels of AEA were similar to 6-fold higher in HD versus healthy lymphocytes, while the other elements of the endocannabinoid system were not affected by HD. Low FAAR activity in HD) lymphocytes was not due to down-regulation of protein expression, but rather to blockage of enzyme activity by a cytosolic and irreversible inhibitor. Finally, pre-HD patients showed defective FAAH activity, as did the brain of HD patients compared with healthy controls. Taken together, our data indicate that FAAH activity in lymphocytes mirrors some of the metabolic changes which take place in the brain, it is a measurable non-genetic peripheral marker that segregates with the HD mutation, and it might serve as a target to test chemicals active on the widespread toxic effects of the mutant protein. (c) 2007 Elsevier Inc. All rights reserved.