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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 >Does tissue transglutaminase play a role in Huntington's disease?
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Does tissue transglutaminase play a role in Huntington's disease?

机译：组织转谷氨酰胺酶是否在亨廷顿氏病中起作用？

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摘要

Tissue transglutaminase (tTG) likely plays a role in numerous processes in the nervous system. tTG posttranslationally modifies proteins by transamidation of specific polypeptide bound glutamines (Glns). This reaction results in the incorporation of polyamines into substrate proteins or the formation of protein crosslinks, modifications that likely have significant effects on neural function. Huntington's disease is a genetic disorder caused by an expansion of the polyglutamine domain in the huntingtin protein. Because a polypeptide bound Gln is the determining factor for a tTG substrate, and mutant huntingtin aggregates have been found in Huntington's disease brain, it has been hypothesized that tTG may contribute to the pathogenesis of Huntington's disease. In vitro, polyglutamine constructs and huntingtin are substrates of tTG. Further, the levels of tTG and TG activity are elevated in Huntington's disease brain and immunohistochemical studies have demonstrated that there is an increase in tTG reactivity in affected neurons in Huntington's disease. These findings suggest that tTG may play a role in Huntington's disease. However in situ, neither wild type nor mutant huntingtin is modified by tTG. Further, immunocytochemical analysis revealed that tTG is totally excluded from the huntingtin aggregates, and modulation of the expression level of tTG had no effect on the frequency of the aggregates in the cells. Therefore, tTG is not required for the formation of huntingtin aggregates, and likely does not play a role in this process in Huntington's disease brain. However, tTG interacts with truncated huntingtin, and selectively polyaminates proteins that are associated with mutant truncated huntingtin. Given the fact that the levels of polyamines in cells is in the millimolar range and the crosslinking and polyaminating reactions catalyzed by tTG are competing reactions, intracellularly polyamination is likely to be the predominant reaction. Polyamination of proteins is likely to effect their function, and therefore it can be hypothesized that tTG may play a role in the pathogenesis of Huntington's disease by modifying specific proteins and altering their function and/or localization. Further research is required to define the specific role of tTG in Huntington's disease.
机译：组织转谷氨酰胺酶（tTG）可能在神经系统的许多过程中起作用。 tTG通过特定多肽结合的谷氨酰胺（Glns）的转酰胺基作用，翻译后修饰蛋白质。该反应导致将多胺掺入底物蛋白质或形成蛋白质交联，这种修饰可能对神经功能产生重大影响。亨廷顿舞蹈病是由亨廷顿蛋白中的聚谷氨酰胺结构域扩展引起的遗传性疾病。因为结合多肽的Gln是tTG底物的决定因素，并且在亨廷顿氏病大脑中发现了亨廷顿突变体聚集体，所以已经假设tTG可能有助于亨廷顿氏病的发病。在体外，聚谷氨酰胺构建体和亨廷顿蛋白是tTG的底物。此外，在亨廷顿氏病大脑中tTG和TG活性水平升高，免疫组织化学研究表明在亨廷顿氏病的受影响神经元中tTG反应性增加。这些发现表明tTG可能在亨廷顿氏病中起作用。然而，就地而言，野生型或突变型亨廷顿蛋白都没有被tTG修饰。此外，免疫细胞化学分析表明，亨廷顿蛋白聚集体中完全排除了tTG，并且调节tTG表达水平对细胞中聚集体的频率没有影响。因此，tTG并不是亨廷顿蛋白聚集体的形成所必需的，并且可能在亨廷顿氏病大脑中的这一过程中不起作用。但是，tTG与截短的亨廷顿蛋白相互作用，并选择性地使与突变的截短的亨廷顿蛋白相关的蛋白质多胺化。考虑到细胞中多胺的水平在毫摩尔范围内，并且由tTG催化的交联和多胺化反应是竞争反应，因此细胞内多胺化可能是主要反应。蛋白质的多胺化可能会影响其功能，因此可以假设tTG可能通过修饰特定蛋白质并改变其功能和/或定位而在亨廷顿氏病的发病机理中发挥作用。需要进一步的研究来确定tTG在亨廷顿氏病中的特定作用。

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