Tau gene mutations and their effects
Tau gene mutations and their effects
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DOI：
10.1002/mds.20539
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发表时间：
2005-08-01
影响因子：
8.6
通讯作者：
Goedert, M
中科院分区：
文献类型：
--
作者：
Goedert, M
Tau是细胞内丝状沉积物的主要成分，其定义了许多神经退行性疾病，包括大部分散发性阿尔茨海默病、进行性核上性麻痹、皮质基底节变性、皮克病和嗜银颗粒病，以及与染色体17（FTDP-17）相关的遗传性额颞叶痴呆和帕金森综合征。很长一段时间以来，人们都不清楚tau蛋白的功能障碍是否伴随着疾病，或者疾病是否伴随着tau蛋白的功能障碍。将Tau中的突变鉴定为FTDP-17的原因已经解决了这个问题。大约一半的已知突变在蛋白质水平上具有主要影响，它们降低了tau蛋白与微管相互作用的能力，并增加了其组装成异常细丝的倾向。其他突变在RNA水平上具有其主要影响，从而扰乱三重复与四重复tau亚型的正常比例。在研究中，这导致了大脑中tau蛋白与四个微管结合重复序列的相对过量产生。几种Tau突变引起类似进行性核上性麻痹、皮质基底节变性或皮克病的疾病。此外，Tau的H1单倍型已被确定为进行性核上性麻痹和皮质基底节变性的重要危险因素。(c)2005年，任上海市人民政府副市长。
Tau is the major component of the intracellular filamentous deposits that define a number of neurodegenerative diseases, including the largely sporadic Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and argyrophilic grain disease, as well as the inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). For a long time, it was unclear whether the dysfunction of tau protein follows disease or whether disease follows the dysfunction of tau protein. The identification of mutations in Tau as the cause of FTDP-17 has resolved this issue. About half of the known mutations have their primary effect at the protein level, and they reduce the ability of tau protein to interact with microtubules and increase its propensity to assemble into abnormal filaments. The other mutations have their primary effect at the RNA level, thus perturbing the normal ratio of three-repeat to four-repeat tau isoforms. Where studied, this resulted in the relative overproduction of tau protein with four microtubule-binding repeats in brain. Several Tau mutations give rise to diseases that resemble progressive supranuclear palsy, corticobasal degeneration, or Pick's disease. Moreover, the H1 haplotype of Tau has been identified as a significant risk factor for progressive supranuclear palsy and corticobasal degeneration. (c) 2005 Movement Disorder Society.