Neurodegenerative disorder FTDP-17-related tau intron 10 +16C → T mutation increases tau exon 10 splicing and causes tauopathy in transgenic mice.
Neurodegenerative disorder FTDP-17-related tau intron 10 +16C → T mutation increases tau exon 10 splicing and causes tauopathy in transgenic mice.
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神经退行性疾病 FTDP-17 相关 tau 内含子 10 +16C → T 突变会增加 tau 外显子 10 剪接并导致转基因小鼠中的 tau 病。
DOI：
10.1016/j.ajpath.2013.03.015
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Mori H.
中科院分区：
文献类型：
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作者：
Umeda T;Yamashita T;Kimura T;Ohnishi K;Takuma H;Ozeki T;Takashima A;Tomiyama T;Mori H.
与17号染色体相关的额颞叶痴呆和帕金森综合征（FTDP-17）是一种由tau基因突变引起的神经退行性疾病。在FTDP-17中发现的许多突变已被证明会影响tau外显子10的体外剪接，这可能会导致外显子10−[3-重复（3R）]和外显子10+[4-重复（4 R）] tau表达的病理性失衡，并导致患者大脑中过度磷酸化tau的细胞内包涵体。然而，没有报道使用具有tau内含子突变的模型小鼠研究该理论。在此，我们产生了携带tau内含子10 + 16 C突变的新的转基因小鼠。我们制备了一个转基因构建体，其中含有最长tau亚型cDNA中外显子10剪接所需的内含子序列。尽管携带没有内含子突变的构建体的小鼠显示出从3R tau到等量的3R和4 R tau的tau同种型的正常发育变化，但具有突变的小鼠在成年阶段显示出高得多的4 R tau水平。4 R tau在老年时选择性地在不溶性脑组分中回收。此外，这些小鼠以年龄依赖性方式显示异常tau磷酸化、突触丧失和功能障碍、记忆障碍、神经胶质活化、缠结形成和神经元丧失。这些发现提供了小鼠模型中的第一个证据，即tau内含子突变诱导的3R和4 R tau失衡可能是tau蛋白病的原因。
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a neurodegenerative disorder caused by mutations in the tau gene. Many mutations identified in FTDP-17 have been shown to affect tau exon 10 splicingin vitro, which presumably causes pathologic imbalances in exon 10−[3-repeat (3R)] and exon 10+[4-repeat (4R)] tau expression and leads to intracellular inclusions of hyperphosphorylated tau in patient brains. However, no reports have investigated this theory using model mice with a tau intronic mutation. Herein, we generated new transgenic mice harboring the tau intron 10 +16C→T mutation. We prepared a transgene construct containing intronic sequences required for exon 10 splicing in the longest tau isoform cDNA. Although mice bearing the construct without the intronic mutation showed normal developmental changes of the tau isoform from 3R tau to equal amounts of 3R and 4R tau, mice with the mutation showed much higher levels of 4R tau at the adult stage. 4R tau was selectively recovered in insoluble brain fractions in their old age. Furthermore, these mice displayed abnormal tau phosphorylation, synapse loss and dysfunction, memory impairment, glial activation, tangle formation, and neuronal loss in an age-dependent manner. These findings provide the first evidence in a mouse model that a tau intronic mutation–induced imbalance of 3R and 4R tau could be a cause of tauopathy.