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1型强直性肌营养不良症中人类脑微管相关tau mRNA成熟的失调

Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1.

作者信息

Sergeant N, Sablonnière B, Schraen-Maschke S, Ghestem A, Maurage C A, Wattez A, Vermersch P, Delacourte A

机构信息

INSERM U422, Groupe VCDN, 1 place de Verdun, 59045 Lille Cedex, France.

出版信息

Hum Mol Genet. 2001 Sep 15;10(19):2143-55. doi: 10.1093/hmg/10.19.2143.

Abstract

Intraneuronal aggregates of hyperphosphorylated tau proteins, referred to as pathological tau, are found in brain areas of demented patients affected by numerous different neurodegenerative disorders. We previously described a particular biochemical profile of pathological tau proteins in myotonic dystrophy type 1 (DM1). This multisystemic disorder is characterized by an unstable CTG repeat expansion in the 3'-untranslated region of the DM protein kinase gene. In the human central nervous system, tau proteins consist of six isoforms that differ by the presence or absence of the alternatively spliced exons 2, 3 and 10. Here we show that the pattern of tau isoforms aggregated in DM1 brain lesions is characteristic. It consists mainly of the aggregation of the shortest human tau isoform. A disruption in normal tau isoform expression consisting of a reduced expression of tau isoforms containing the exon 2 was observed at both the mRNA and protein levels. Large expanded CTG repeats were detected and showed marked somatic heterogeneity between DM1 cases and in cortical brains regions analysed. Our data suggest a relationship between the CTG repeat expansion and the alteration of tau expression showing that DM1 is a peculiar tauopathy.

摘要

在受多种不同神经退行性疾病影响的痴呆患者脑区中发现了高磷酸化tau蛋白的神经元内聚集体,即病理性tau。我们之前描述了1型强直性肌营养不良(DM1)中病理性tau蛋白的一种特殊生化特征。这种多系统疾病的特征是DM蛋白激酶基因3'非翻译区的CTG重复序列不稳定扩增。在人类中枢神经系统中,tau蛋白由六种异构体组成,它们因选择性剪接外显子2、3和10的有无而不同。在这里,我们表明在DM1脑损伤中聚集的tau异构体模式具有特征性。它主要由最短的人类tau异构体的聚集组成。在mRNA和蛋白质水平均观察到正常tau异构体表达的破坏,即包含外显子2的tau异构体表达减少。检测到大量扩增的CTG重复序列,并且在DM1病例之间以及所分析的皮质脑区中显示出明显的体细胞异质性。我们的数据表明CTG重复序列扩增与tau表达改变之间存在关联,表明DM1是一种特殊的tau蛋白病。

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