The N-terminal disease-associated R5L Tau mutation increases microtubule shrinkage rate due to disruption of microtubule-bound Tau patches.
The N-terminal disease-associated R5L Tau mutation increases microtubule shrinkage rate due to disruption of microtubule-bound Tau patches.
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DOI：
10.1016/j.jbc.2022.102526
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发表时间：
2022-11
影响因子：
4.8
通讯作者：
Berger, Christopher L.
中科院分区：
文献类型：
--
作者：
Cario, Alisa;Wickramasinghe, Sanjula P.;Rhoades, Elizabeth;Berger, Christopher L.
神经元微管细胞骨架的调节是通过微管相关蛋白（MAP）的协调来实现的。MAP-Tau是轴突中最丰富的MAP，其功能是调节运动运动，参与信号级联，以及直接介导微管动力学。Tau失调与一类称为Tau病的神经退行性疾病相关，包括进行性核上性麻痹、皮克病和阿尔茨海默病。Tau中的许多疾病相关突变发现于C-末端微管结合结构域中。这些突变降低了微管结合亲和力，并被认为降低了微管稳定性，导致疾病。N-末端疾病相关突变也存在，但其下游效应的机制细节并不清楚。在这里，我们调查的效果进行性核上麻痹相关的N-末端R5 L突变对Tau介导的微管动力学使用体外重建系统。我们表明，R5 L突变不改变Tau与微管蛋白的相互作用，通过荧光相关光谱。使用全内反射荧光显微镜，我们确定R5 L突变对微管生长速率，灾难频率或救援频率没有影响。相反，R5 L突变增加微管收缩率。我们确定这是由于破坏了Tau斑块，已知在GDP-微管晶格上形成的更大顺序的Tau复合物。总之，这些结果提供了深入了解Tau补丁在介导微管动力学中的作用，并提出了一种新的机制，通过该机制，N-末端投射结构域中的突变降低微管稳定性。
Regulation of the neuronal microtubule cytoskeleton is achieved through the coordination of microtubule-associated proteins (MAPs). MAP-Tau, the most abundant MAP in the axon, functions to modulate motor motility, participate in signaling cascades, as well as directly mediate microtubule dynamics. Tau misregulation is associated with a class of neurodegenerative diseases, known as tauopathies, including progressive supranuclear palsy, Pick's disease, and Alzheimer's disease. Many disease-associated mutations in Tau are found in the C-terminal microtubule-binding domain. These mutations decrease microtubule-binding affinity and are proposed to reduce microtubule stability, leading to disease. N-terminal disease-associated mutations also exist, but the mechanistic details of their downstream effects are not as clear. Here, we investigate the effect of the progressive supranuclear palsy–associated N-terminal R5L mutation on Tau-mediated microtubule dynamics using an in vitro reconstituted system. We show that the R5L mutation does not alter Tau interactions with tubulin by fluorescence correlation spectroscopy. Using total internal reflection fluorescence microscopy, we determined that the R5L mutation has no effect on microtubule growth rate, catastrophe frequency, or rescue frequency. Rather, the R5L mutation increases microtubule shrinkage rate. We determine this is due to disruption of Tau patches, larger order Tau complexes known to form on the GDP-microtubule lattice. Altogether, these results provide insight into the role of Tau patches in mediating microtubule dynamics and suggesting a novel mechanism by which mutations in the N-terminal projection domain reduce microtubule stability.
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影响因子：
9.9
作者：
Borroni, B.;Malinverno, M.;Padovani, A.
通讯作者：
Padovani, A.
DOI：
10.1083/jcb.115.3.717
发表时间：
1991-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Butner KA;Kirschner MW
通讯作者：
Kirschner MW
Tau通过调节动力蛋白和动力蛋白团队施加的力来指导细胞内贩运。
DOI：
10.1111/tra.12537
发表时间：
2018-03
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Chaudhary AR;Berger F;Berger CL;Hendricks AG
通讯作者：
Hendricks AG
DOI：
10.1083/jcb.202012144
发表时间：
2021-10-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Farmer V;Arpağ G;Hall SL;Zanic M
通讯作者：
Zanic M
DOI：
10.1073/pnas.85.11.4051
发表时间：
1988-06-01
影响因子：
11.1
作者：
GOEDERT, M;WISCHIK, CM;KLUG, A
通讯作者：
KLUG, A