Role of Tau in Microtubule Stability in Adult Neurons

Tau 在成年神经元微管稳定性中的作用

基本信息

批准号：
10214857
负责人：
PETER W. BAAS
金额：
$ 41.64万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214857
关键词：
Adolescent Adult Alzheimer&apos s Disease Anatomy Axon Basic Science Behavioral Binding Binding Proteins Binding Sites Brain Cell Culture Techniques Complex Defect Disease Distal Image Individual Investigation Knockout Mice Life Light Literature MAPT gene Medical Microtubule Stabilization Microtubule-Associated Proteins Microtubules Minus End of the Microtubule Modeling Mus Neurodegenerative Disorders Neuroglia Neurons Paper Pharmaceutical Preparations Physiological Principal Investigator Property Proteins Publishing RNA Interference Research Research Personnel Rodent Role Science Sorting - Cell Movement System Tauopathies Testing Tube Tubulin Uncertainty Viral Work base depolymerization fetal in vivo knock-down loss of function mouse model overexpression prevent small hairpin RNA tau Proteins tau function tau mutation theories therapy development

项目摘要

PROJECT SUMMARY / ABSTRACT Tau, a fibrous microtubule-associated protein concentrated in the axon, binds to microtubules, thereby influencing its properties. For decades, the prevailing theory has been that tau stabilizes microtubules in the axon. This is based on test tube studies showing that excess tau can indeed stabilize microtubules, as well as overexpression studies showing this to be the case in non-neuronal cells as well. Disease researchers are so invested in the idea of tau as a microtubule stabilizer that work is underway to use microtubule-stabilizing drugs to treat diseases such as Alzheimer’s, in which tau loses its association with microtubules. Recent published work of the Principal Investigator has challenged this dogma, building on evidence that tau is enriched on the labile domains of microtubules in the axon than on the stable domains. Moreover, in that work, when tau was depleted from the neuron with RNA interference, there was a loss of microtubule mass but not due to destabilization of the stable domains of the microtubules. Rather, there was a preferential loss of the labile domains, with the remaining portion of the labile domains actually becoming more stable rather than less stable. Additional studies suggested that tau prevents the labile domain from becoming stable by outcompeting genuine microtubule-stabilizers such as MAP6, and also promotes the assembly of the labile domain. This is a strikingly different scenario from the one that has become so established in the scientific literature, and potentially transformational to both the basic sciences and medical sciences of tau. However, all of that work was done on developing rodent neurons in culture, with the very real possibility that the situation is not the same in adult brain. In this proposal, the Principal Investigator seeks to test whether the findings hold true in adult mouse brain, using viral-driven RNA interference to lower tau levels. From there, studies are proposed to delve into the proposed competition between tau and genuine microtubule stabilizers such as MAP6 by ectopically expressing fluorescently tagged versions of them in non-neuronal cells in which binding of these proteins to microtubules can be readily visualized. Collectively, these studies will contribute significantly to understanding of tau, a crucial protein for both normal functioning of the axon and for disease, and will open the door toward mechanism-based therapies to rectify the ill effects of tau loss-of-function in disease.

项目摘要 /摘要 tau是一种纤维微管相关的蛋白浓缩在轴突中的蛋白，与微管结合，从而结合影响其特性。几十年来，普遍的理论一直是Tau稳定了微管轴突。这是基于试管研究，表明超过tau确实可以稳定微管以及过表达的研究表明，在非神经元细胞中也是如此。疾病研究人员是如此投资于tau作为微管稳定剂的想法，正在使用微管稳定药物为了治疗诸如阿尔茨海默氏症之类的疾病，其中tau失去了与微管的关联。最新出版首席调查员的工作对这一教条提出了质疑，这是基于证据表明Tau丰富的证据轴突中微管的不稳定结构域，而不是稳定域中。而且，在这项工作中，tau是从神经元中耗尽的RNA干扰，微管质量损失，但不是由于微管的稳定结构域的不稳定。相反，不稳定的首选损失域，不稳定域的其余部分实际上变得更加稳定，而不是稳定。其他研究表明，tau可以通过胜任真实的人来防止不稳定的域变得稳定微管稳定器（例如MAP6），还促进了不稳定域的组装。这是一个惊人的与在科学文献中已经建立的那种情况不同的情况，并有可能转化为Tau的基本科学和医学科学。但是，所有这些工作都完成了在培养物中发展啮齿动物神经元，很有可能在成年大脑中情况不一样。在此提案中，首席研究人员试图测试这些发现在成年小鼠大脑中是否成立，并使用病毒驱动的RNA干扰较低的Tau水平。从那里，提出了研究来研究提议的 tau和真正的微管稳定剂（例如MAP6）之间的竞争通过异位表达它们在非神经元细胞中的荧光标记版本，其中这些蛋白质与微管结合可以很容易地可视化。总的来说，这些研究将有助于理解Tau，这是一种关键轴突正常功能和疾病的正常功能，并将打开基于机制的大门纠正tau功能丧失疾病的不良影响的疗法。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mini-review: Microtubule sliding in neurons.

DOI：
10.1016/j.neulet.2021.135867
发表时间：
2021-05-14
期刊：
Neuroscience letters
影响因子：
2.5
作者：
Guha S;Patil A;Muralidharan H;Baas PW
通讯作者：
Baas PW

Therapeutic Strategies for Mutant SPAST-Based Hereditary Spastic Paraplegia.

DOI：
10.3390/brainsci11081081
发表时间：
2021-08-18
期刊：
Brain sciences
影响因子：
3.3
作者：
Mohan N;Qiang L;Morfini G;Baas PW
通讯作者：
Baas PW

A cellular approach to understanding and treating Gulf War Illness.

DOI：
10.1007/s00018-021-03942-3
发表时间：
2021-11
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
0
作者：
通讯作者：

Modeling gain-of-function and loss-of-function components of SPAST-based hereditary spastic paraplegia using transgenic mice.

使用转基因小鼠对基于 SPAST 的遗传性痉挛性截瘫的功能获得和功能丧失成分进行建模。

DOI：
10.1093/hmg/ddab367
发表时间：
2022
期刊：
Human molecular genetics
影响因子：
3.5
作者：
Piermarini,Emanuela;Akarsu,Seyma;Connors,Theresa;Kneussel,Matthias;Lane,MichaelA;Morfini,Gerardo;Karabay,Arzu;Baas,PeterW;Qiang,Liang
通讯作者：
Qiang,Liang

Is Gulf War Illness a prolonged early phase tauopathy?