HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism
HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism
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DOI：
10.1093/hmg/ddi319
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发表时间：
2005-10-01
影响因子：
3.5
通讯作者：
MacDonald, ME
中科院分区：
文献类型：
--
作者：
Seong, IS;Ivanova, E;MacDonald, ME
导致亨廷顿病（HD）的“扩展”HD CAG重复序列编码亨廷顿蛋白中的多聚谷氨酰胺束，其首先靶向中型多刺纹状体神经元的死亡。与N-甲基-D-天冬氨酸（NMDA）Ca 2+信号相关的线粒体能量学长期以来一直与这种神经元特异性有关，这意味着亨廷顿蛋白在线粒体能量代谢中的不可或缺的作用。作为对这一假设的遗传学检验，我们已经寻找了在内源性亨廷顿蛋白中表达的HD CAG重复序列的长度与线粒体ATP产生之间的关系。在STHdh（Q111）敲入的纹状体细胞中，幼年发作的HD CAG重复与线粒体ATP低和线粒体ADP摄取减少相关。这种代谢抑制与通过NMDA受体的Ca 2+内流增强有关，当阻断时，导致细胞[ATP/ADP]增加。然后，我们在40个人淋巴母细胞系中评估了[ATP/ADP]，这些细胞系具有非HD CAG长度（9-34个单位）或HD致病等位基因（35-70个单位）。该分析揭示了在非HD和HD范围中与两个等位基因HD CAG重复中的较长者的负相关。因此，多聚谷氨酰胺道亨廷顿蛋白似乎调节线粒体ADP磷酸化的钙依赖性过程，满足遗传标准的HD触发的发病机制，从而确定了一个基本的生物参数细胞的能量状态，这可能有助于精致的脆弱性纹状体神经元HD。此外，这种多态性可以确定非HD范围内的能量状态的证据表明，它应该被测试作为一个潜在的生理调节剂在健康和疾病。
The 'expanded' HD CAG repeat that causes Huntington's disease (HD) encodes a polyglutamine tract in huntingtin, which first targets the death of medium-sized spiny striatal neurons. Mitochondrial energetics, related to N-methyl-d-aspartate (NMDA) Ca2+-signaling, has long been implicated in this neuronal specificity, implying an integral role for huntingtin in mitochondrial energy metabolism. As a genetic test of this hypothesis, we have looked for a relationship between the length of the HD CAG repeat, expressed in endogenous huntingtin, and mitochondrial ATP production. In STHdh(Q111) knock-in striatal cells, a juvenile onset HD CAG repeat was associated with low mitochondrial ATP and decreased mitochondrial ADP-uptake. This metabolic inhibition was associated with enhanced Ca2+-influx through NMDA receptors, which when blocked resulted in increased cellular [ATP/ADP]. We then evaluated [ATP/ADP] in 40 human lymphoblastoid cell lines, bearing non-HD CAG lengths (9-34 units) or HD-causing alleles (35-70 units). This analysis revealed an inverse association with the longer of the two allelic HD CAG repeats in both the non-HD and HD ranges. Thus, the polyglutamine tract in huntingtin appears to regulate mitochondrial ADP-phosphorylation in a Ca2+-dependent process that fulfills the genetic criteria for the HD trigger of pathogenesis, and it thereby determines a fundamental biological parameter-cellular energy status, which may contribute to the exquisite vulnerability of striatal neurons in HD. Moreover, the evidence that this polymorphism can determine energy status in the non-HD range suggests that it should be tested as a potential physiological modifier in both health and disease.