Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease.
Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease.
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DOI：
10.1021/acs.biochem.6b00936
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发表时间：
2017-03-07
期刊：
影响因子：
2.9
通讯作者：
Legleiter J
中科院分区：
文献类型：
--
作者：
Adegbuyiro A;Sedighi F;Pilkington AW 4th;Groover S;Legleiter J
几种遗传性神经和神经肌肉疾病是由三核苷酸重复序列异常扩增引起的。迄今为止，已经有十种这种三核苷酸重复疾病与编码谷氨酰胺(Q)的密码子CAG的扩增有关。对于这些多聚谷氨酰胺（polyQ）疾病，存在疾病所需的CAG重复的临界阈值长度，并且超过该阈值的进一步扩展与发病年龄和症状严重程度相关。翻译蛋白中的PolyQ扩增促进其自组装成各种低聚物和纤维聚集体，这些聚集体积累成与每种疾病相关的标志性蛋白质包涵体。在这里，我们回顾了扩展的多q束蛋白的聚集机制，扩展的多q从单体到纤维聚集体的结构后果，蛋白质环境和翻译后修饰对聚集的影响，以及脂质膜在聚集中的潜在作用。由于这些疾病背后的致病机制通常被归类为毒性功能的获得或正常蛋白质功能的丧失，因此我们也将讨论与突变多q束相关的一些毒性机制。
Several hereditary neurological and neuromuscular diseases are caused by an abnormal expansion of trinucleotide repeats. To date, there have been ten of these trinucleotide repeat disorders associated with an expansion of the codon CAG encoding glutamine (Q). For these polyglutamine (polyQ) diseases, there is a critical threshold length of the CAG repeat required for disease, and further expansion beyond this threshold is correlated with age of onset and symptom severity. PolyQ expansion in the translated proteins promotes their self-assembly into a variety of oligomeric and fibrillar aggregate species that accumulate into the hallmark proteinaceous inclusion bodies associated with each disease. Here, we review aggregation mechanisms of proteins with expanded polyQ-tracts, structural consequences of expanded polyQ ranging from monomers to fibrillar aggregates, the impact of protein context and post translational modifications on aggregation, and a potential role for lipids membranes in aggregation. As the pathogenic mechanisms that underlie these disorders are often classified as either a gain of toxic function or loss of normal protein function, some toxic mechanisms associated with mutant polyQ tracts will also be discussed.
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