Small changes, big impact: posttranslational modifications and function of huntingtin in Huntington disease.
Small changes, big impact: posttranslational modifications and function of huntingtin in Huntington disease.
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DOI：
10.1177/1073858410390378
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发表时间：
2011-10
期刊：
影响因子：
--
通讯作者：
Hayden MR
中科院分区：
文献类型：
--
作者：
Ehrnhoefer DE;Sutton L;Hayden MR
亨廷顿病（Huntington disease，HD）是由亨廷顿蛋白（huntingtin，htt）中的多聚谷氨酰胺（polyglutamine，polyglutamine）链延长引起的神经退行性疾病。Htt通常经历不同的翻译后修饰（PTM），包括磷酸化、SUMO化、泛素化、乙酰化、蛋白水解切割和棕榈酰化。在HD突变的存在下，一些PTM被显著改变，并可导致临床表型的变化。速率限制性PTM定义为可对动物模型中的表型产生显著影响的PTM。例如，阻止D586处的蛋白质水解以及S13和S16处的组成性磷酸化可以消除HD表型特征的表达。因此，参与这些修饰的酶，如胱天蛋白酶-6、IκB激酶（IKK）复合物和仍待表征的磷酸酶，代表了HD有希望的治疗靶点。识别和测试PTM的特定调节剂现在构成了下一个重大挑战，以便进一步验证这些目标并朝着基于机制的HD治疗目标前进。
Huntington disease (HD) is a neurodegenerative disorder caused by an elongated polyglutamine tract in huntingtin (htt). Htt normally undergoes different posttranslational modifications (PTMs), including phosphorylation, SUMOylation, ubiquitination, acetylation, proteolytic cleavage and palmitoylation. In the presence of the HD mutation, some PTMs are significantly altered and can result in changes in the clinical phenotype. A rate limiting PTM is defined as one which can result in significant effects on the phenotype in animal models. For example the prevention of proteolysis at D586 as well as constitutive phosphorylation at S13 and S16 can obviate the expression of phenotypic features of HD. The enzymes involved in these modifications such as caspase-6, the IκB kinase (IKK) complex and still to be characterized phosphatases therefore represent promising therapeutic targets for HD. Identifying and testing specific modulators of PTMs now constitutes the next big challenge in order to further validate these targets and proceed towards the goal of a mechanism-based treatment for HD.
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