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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Cross linking of polyglutamine domains catalyzed by tissue transglutaminase is greatly favored with pathological-length repeats: does transglutaminase activity play a role in (CAG)(n)/Q(n)-expansion diseases?
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Cross linking of polyglutamine domains catalyzed by tissue transglutaminase is greatly favored with pathological-length repeats: does transglutaminase activity play a role in (CAG)(n)/Q(n)-expansion diseases?

机译：组织转谷氨酰胺酶催化的聚谷氨酰胺结构域的交联在病理学长度上是非常受欢迎的：转谷氨酰胺酶活性是否在（CAG）（n）/ Q（n）-扩展疾病中起作用？

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摘要

Protein aggregates are a hallmark of Huntington's disease (HD) and other inherited neurodegenerative diseases caused by an elongated (CAG)(n) repeat in the genome and to a corresponding increase in the size of the Q(n) domain in the expressed protein. When the protein associated with HD (huntingtin) contains <35 Q repeats disease does not occur. However, an n>/=40 leads to disease. Some investigators have proposed that aggregates in the nuclei of affected cells are toxic, but other workers have suggested that the aggregates may be neutral or even protective. Whether or not they are toxic, an understanding of the processes whereby the aggregates develop may shed light on the neuropathological processes involved in the (CAG)(n)/Q(n)-expansion disorders. Q(n) domains have a tendency to non-covalently self align as 'polar zippers' rendering them less soluble, but evidence that such polar zippers occur in the aggregates in intact HD brain has so far been limited. The human brain contains at least three Ca(2+)-dependent enzymes (transglutaminases, TGases) that catalyze protein cross-linking reactions, namely TGase 1, TGase 2 (tissue transglutaminase, tTGase) and TGase 3. Q(n) aggregates have been found by several groups to be excellent substrates of tTGase. Moreover, the activity toward the Q(n) domains increases greatly as n is increased to 40 or beyond. tTGase mRNA and total TGase activity are elevated in HD brain. Moreover, some evidence suggests that Ca(2+) homeostasis is disrupted in HD brain. We propose that the combination of increased huntingtin (or huntingtin fragment containing the Q(n) domain) in the nucleus, increased the ability of the Q(n) domains to act as substrate, increased Ca(2+) levels and increased inherent TGase activity all contribute to increased cross-linking of proteins in HD brain. At first the proteasome machinery can recognize and degrade the cross-linked proteins, but over time the proteasome machinery may be overwhelmed and protein aggregates will accumulate.
机译：蛋白质聚集体是亨廷顿舞蹈病（HD）和其他遗传性神经退行性疾病的标志，这种疾病是由基因组中的延长（CAG）（n）重复序列引起的，并导致表达的蛋白质Q（n）结构域大小相应增加。当与HD相关的蛋白（亨廷顿蛋白）的Q值小于35时，不会发生疾病。但是，n> / = 40会导致疾病。一些研究者提出，受影响细胞核中的聚集体是有毒的，但其他研究人员则提出，聚集体可能是中性的，甚至是保护性的。无论它们是否有毒，对聚集体形成过程的理解可能有助于阐明（CAG）（n）/ Q（n）-膨胀性疾病所涉及的神经病理学过程。 Q（n）域具有非共价自我对齐的趋势，因为“极性拉链”使它们的溶解度降低，但是迄今为止，这种极性拉链存在于完整HD脑中的聚集物中的证据仍然有限。人脑至少包含三种催化蛋白质交联反应的Ca（2+）依赖酶（转谷氨酰胺酶，TGase），分别是TGase 1，TGase 2（组织转谷氨酰胺酶，tTGase）和TGase3。Q（n）聚集体具有几组人发现它们是tTGase的优良底物。此外，随着n增加到40或更大，对Q（n）域的活性大大增加。 HD脑中tTGase mRNA和总TGase活性升高。此外，一些证据表明，高清脑中Ca（2+）稳态被破坏。我们建议增加核中亨廷顿蛋白（或包含Q（n）域的亨廷顿片段），Q（n）域充当底物，Ca（2+）水平和固有TGase增加的能力的组合活性都有助于增加高清大脑中蛋白质的交联。起初，蛋白酶体机制可以识别和降解交联的蛋白质，但是随着时间的流逝，蛋白酶体机制可能会不堪重负，并且蛋白质聚集体会积累。

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