FTDP-17 tau mutations induce distinct effects on aggregation and microtubule interactions.
FTDP-17 tau mutations induce distinct effects on aggregation and microtubule interactions.
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DOI：
10.1021/bi3010818
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发表时间：
2012-10-30
期刊：
影响因子：
2.9
通讯作者：
Gamblin TC
中科院分区：
文献类型：
--
作者：
Combs B;Gamblin TC
tau基因中的FTDP-17突变导致以微管相关蛋白tau的病理性聚集为特征的早发性额颞叶痴呆。Tau聚集与脑中某些区域的局部萎缩的进展和严重程度密切相关。这些突变主要位于tau蛋白的微管结合重复区或其附近，对蛋白质的影响截然不同。一些突变与诸如聚集增加、过度磷酸化、mRNA剪接缺陷以及与微管的相互作用减少等效应有关。考虑到突变的差异效应，与FTDP-17相关的病理学也可能有很大差异，这可能并不奇怪。尽管有这种多样性，但几种突变通常可互换地用作Tau蛋白病的体外和体内模型的聚集诱导剂。我们产生了12个FTDP-17突变的重组形式，这些突变是根据其对蛋白质的电荷、疏水性和二级结构的预测影响而选择的。然后，我们研究了突变对蛋白质体外聚集特性及其稳定微管组装能力的影响。该组突变诱导的聚集总量，聚集的动力学，和细丝形态非常不同的影响。其中几种突变抑制了tau的微管稳定能力，而其他突变与野生型tau相比几乎没有影响。这些结果表明，FTDP-17突变之间的疾病进展机制可能不同，并且不同突变的影响在所有模型系统中可能不相等。
FTDP-17 mutations in the tau gene lead to early-onset frontotemporal dementias characterized by the pathological aggregation of the microtubule-associated protein tau. Tau aggregation is closely correlated with the progression and severity of localized atrophy of certain regions in the brain. These mutations are primarily located in or near the microtubule-binding repeat regions of tau and can have vastly different effects on the protein. Some mutations have been linked to effects such as increased aggregation, hyperphosphorylation, defects in mRNA splicing, and decreased interaction with microtubules. Given the differential effects of the mutations it may not be surprising that the pathology associated with FTDP-17 can vary widely as well. Despite this variety, several of the mutations are commonly used interchangeably as aggregation inducers for in vitro and in vivo models of tauopathies. We generated recombinant forms of 12 FTDP-17 mutations chosen for their predicted effects on the charge, hydrophobicity, and secondary structure of the protein. We then examined the effects that the mutations had on the properties of in vitro aggregation of the protein and its ability to stabilize microtubule assembly. The group of mutations induced very different effects on the total amount of aggregation, the kinetics of aggregation, and filament morphology. Several of the mutations inhibited the microtubule-stabilization ability of tau while others had very little effect compared to wild-type tau. These results indicate that the mechanisms of disease progression may differ among FTDP-17 mutations and that the effects of the varying mutations may not be equal in all model systems.
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DOI：
10.1083/jcb.201007161
发表时间：
2011-02-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gauthier-Kemper A;Weissmann C;Golovyashkina N;Sebö-Lemke Z;Drewes G;Gerke V;Heinisch JJ;Brandt R
通讯作者：
Brandt R
影响因子：
2.5
作者：
Grover, A;DeTure, M;Hutton, M
通讯作者：
Hutton, M
影响因子：
11.4
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA
影响因子：
3.5
作者：
Hasegawa, M;Smith, MJ;Goedert, M
通讯作者：
Goedert, M
影响因子：
2.9
作者：
Gamblin, TC;Berry, RW;Binder, LI
通讯作者：
Binder, LI