Mutations in the tau gene that cause an increase in three repeat tau and frontotemporal dementia
Mutations in the tau gene that cause an increase in three repeat tau and frontotemporal dementia
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DOI：
10.1093/brain/awg090
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发表时间：
2003-04-01
期刊：
影响因子：
14.5
通讯作者：
Schofield, PR
中科院分区：
文献类型：
--
作者：
Stanford, PM;Shepherd, CE;Schofield, PR
大多数额颞叶痴呆 (FTD) 病例大脑中没有 tau 沉积，但 tau 基因突变导致类似的临床表型，在神经病理病变中出现不溶性 tau 沉积。我们报告了两个 tau 基因突变，位于紧随外显子 10 茎环结构之后的内含子序列中 +19 和 +29 位，与 FTD 分离。外显子捕获实验表明，这些基因突变改变了外显子 10 的剪接，并增加了具有三个微管结合域（三个重复 tau）的 tau 异构体。诱变实验表明，+19 突变导致了 tau 蛋白三个重复序列的增加，可能是通过改变在该基因区域发现的内含子沉默调节器序列元件来实现的。微管结合实验表明，随着三个重复 tau 蛋白的数量增加和四个重复 tau 蛋白的数量减少，微管组装显着减少。一例可进行脑部尸检。对可溶性 tau 亚型类型的分析表明，三个重复 tau 有所增加，而带有外显子 3 插入的 tau 亚型则不存在。在组织部分中没有分离出不溶性 tau，这与不存在 tau 阳性组织病理学一致。 tau 蛋白降解产物也有所增加，表明蛋白水解作用增强。 tau 分解产物的增加与组织学鉴定的 TUNEL 和激活的 caspase-3 阳性神经元有关。这些研究表明，在紧邻外显子 10 茎环的内含子区域中 tau 基因突变的病例中，可溶性三重复 tau 的增加可能是 FTD 的原因。这些 FTD 病例具有 tau 异构体（没有外显子 3 插入），不会形成异常聚集体，并且似乎更容易蛋白水解。 tau 蛋白水解的增加与细胞凋亡证据的增加相关。这种神经变性机制可能更适用于大多数 FTD 病例，这些病例不会积累不溶性 tau 沉积物。
The majority of cases with frontotemporal dementia (FTD) have no tau deposition in the brain, yet mutations in the tau gene lead to a similar clinical phenotype with insoluble tau depositing in neuropathological lesions. We report two tau gene mutations at positions +19 and +29, in the intronic sequences immediately following the stem loop structure in exon 10, which segregate with FTD. Exon-trapping experiments showed that these gene mutations alter the splicing out of exon 10 and produce an increase in tau isoforms with three microtubule binding domains (three repeat tau). Mutagenesis experiments demonstrated that the +19 mutation was responsible for the increase in three repeat tau, possibly by altering an intron silencer modulator sequence element found at this region of the gene. Microtubule binding experiments revealed a significant decrease in microtubule assembly with increasing amounts of three and decreasing amounts of four repeat tau. Brain autopsy was available in one case. Analysis of the type of soluble tau isoforms revealed an increase in three repeat tau and an absence of tau isoforms with exon 3 inserts. No insoluble tau was isolated in the tissue fractions, consistent with the absence of tau-positive histopathology. There was also an increase in tau degradation products suggestive of increased proteolysis. This increase in tau breakdown products was associated with TUNEL- and activated caspase-3-positive neurons identified histologically. These studies show that increases in soluble three repeat tau can be responsible for FTD in cases with tau gene mutations in the intronic region immediately adjacent to the stem loop in exon 10. These cases of FTD have tau isoforms (without exon 3 inserts) that do not form abnormal aggregates and appear more prone to proteolysis. The increase in tau proteolysis was associated with increased evidence of apoptosis. This mechanism of neurodegeneration may be more applicable to the majority of FTD cases, which do not accumulate insoluble tau deposits.