责编 | 兮
女性得阿兹海默病（Alzheimer’s disease，AD）的概率要比男性高大约两倍。但女性易患AD的原因还没有科学确切的解释。其中一个可能原因是女性大脑中一种名为tau的蛋白表达量较之男性更高。在大脑中，tau对维持神经元的正常结构及功能有着至关重要的作用。正常生理状态下， 当神经细胞不再需要tau时，它会被机体降解分离。但是在阿兹海默病 （Alzheimer’s disease，AD）以及以tau蛋白异常沉积为主要病理机制的一系列疾病中 （tauopathies）， tau 的清除过程出现问题，导致这些本该被降解的tau 蛋白在神经细胞中异常聚合， 进而干扰神经细胞的正常工作，最终导致神经细胞的功能丧失，甚至死亡。
所以是什么原因导致tau的清除过程出现问题呢？在降解过程中，tau首先会被泛素化（ubiquitination）。Tau的泛素化及去泛素化 (deubiquitination)受到一系列酶的平衡调控， 其中包括去泛素化酶。如果此调控过程出现问题，就有可能导致tau在阿兹海默病中异常沉积。
2022年10月4日，来自美国凯斯西储大学医学院病理系（Case Western Reserve University, Department of Pathology）的David E. Kang和Jung A. Woo（第一作者为颜妍）的研究团队在Cell上发表题为X-linked Ubiquitin-Specific Peptidase 11 Increases Tauopathy Vulnerability in Women的文章。文章发现在女性大脑中，一种名为USP11的蛋白表达量高于男性，导致女性较之男性有更多的异常tau蛋白沉积， 从而增大了女性得阿兹海默病的风险。
首先作者们通过无偏差的USPs siRNA筛选，发现降低USP11的表达量可减少tau的表达。通过细胞及体外蛋白实验作者们发现USP11可调控tau去泛素化
（特别是lysine-281位点）
，促进tau在细胞中的聚合。
在阿兹海默病和额颞叶痴呆症中
（Frontotemporal dementia，
FTD
）
，作者们通过脑组织切片免疫荧光染色发现USP11去泛素化酶的增高导致tau在大脑中异常聚合从而增大了得AD的风险。在没有痴呆症的对照组中， 组织免疫荧光染也发现USP11 在女性中的表达量高于男性，相似的结果也在野生型老鼠中被证实。
最后作者利用tau
P301S
突变基因小鼠，通过敲除usp11基因，研究内源性usp11对病理性tau所引起的相关病变的影响。研究发现，从病理性tau引起的相关变化及对记忆障碍的影响来看，虽然敲除usp11对雄性动物也有保护作用，但其效果远不如对雌性动物的保护作用强。
总的来说， 从实验结果推断，
女性因为有过多的USP11去泛素化酶的表达，导致她们更加容易患上老年痴呆症。但是作者们也对老鼠模型是否能能完全模拟tau的病理改变在人类中存在的性别差异持有谨慎态度。作者希望更多的科研工作者及药物开发专业人员能借此机会开发研究能抑制USP11活性的药物，从而减少阿兹海默病在女性中的发病率。
以下为通讯作者David E. Kang的采访稿：
1)What was the motivation for your study?
In the brain, there is an important protein called tau that helps maintain the proper structure of nerve cells. When a particular tau protein is no longer needed for its nerve cell’s function, however, it is normally designated for destruction and clearance. Sometimes this clearance process is disrupted, which causes tau to pathologically aggregate inside nerve cells. This leads to nerve cell destruction in conditions called tauopathies, the most well-known of which is Alzheimer’s disease (AD). The process of eliminating excess tau begins with the addition of a chemical tag called ubiquitin to the tau protein. The presence of ubiquitin on tau is regulated by a balanced system of enzymes that either add or remove the ubiquitin tag. Since dysfunction of this balanced process can lead to abnormal accumulation of tau in AD, we searched for reasons why this might happen. Specifically, we looked for increased activity of the enzymatic system controlling the removal of the ubiquitin tag, since over-activation of this side of the balance could lead to pathological tau accumulation. We reasoned that if this could be identified, then it could provide a basis for the development of new medicine that could restore the proper balance of tau levels in the brain.
2)What is the significance of these findings in simple terms? What are the implications? What would you hope a general audience might take away from these findings, and what should they NOT take away?
The major significance of our study is that through an unbiased discovery approach, we discovered that the USP11 enzyme confers greater vulnerability to AD in women by causing abnormally high tau aggregation in their brains. It has long been recognized that about twice as many women as men are affected by AD, and also that women display higher levels of tau aggregation in the brain than men. However, the reason for this has been a mystery. Now, we have found that both female mice and human women naturally express higher levels of USP11 in the brain than males, and also that USP11 levels correlate strongly with brain tau pathology in females but not males. Furthermore, when we genetically eliminated USP11 in a mouse model of brain tau pathology, females were preferentially protected from tau pathology and cognitive impairment. Males were also protected against tau pathology in the brain but not nearly to the extent as in females. Thus, we can conclude that excessive activity of the USP11 enzyme in females drives their increased susceptibility to tau pathology in AD.
In terms of implications, the good news is that USP11 is an enzyme, and enzymes can traditionally be inhibited pharmacologically. Our hope is to develop a medicine that works in this way, in order to protect women from the higher risk of developing AD.
So, the takeaway message from this study is that we now understand one significant reason why women are generally more vulnerable to AD than men. Armed with this knowledge, the field can now address this problem from a novel perspective. This is not to say that USP11 is the only cause for heightened AD susceptibility in women. Indeed, there are other known and unknown factors that contribute to this effect. However, we are particularly excited about this finding because it provides a basis for the development of new neuroprotective medicines.
3)Can you describe in simple terms how your study is novel?
The novelty of our study resides in the discovery that excessive USP11 enzyme level in the brains of women causes the removal of too many ubiquitin tags from tau, which prevents the normal elimination of tau from nerve cells. When excess tau is not eliminated, it forms pathological aggregates that contribute to AD. Our data show that women experience this more than men because the gene for USP11 resides on the X chromosome. Women have two X chromosomes, while men only have one. Although large parts of the extra X chromosome in women are normally inactivated, this is far from a complete process. Indeed, the amount of X-chromosome inactivation varies across women and even across cells within the same woman. As a result, various parts of the extra X chromosome remain active in any given cell, such that the genes encoded by those parts of the X chromosome are expressed at higher than normal levels. This is very likely why women have higher levels of USP11 in their brains than men, and as a result, do not eliminate tau at the same rate as men.
4)Were you especially surprised by anything you found? Was there anything else that you found particularly notable about your findings, or anything else in general you'd like to add?
We performed an unbiased screen simply to identify enzymes that could remove ubiquitin from tau, and we were not expecting to find a cause for increased AD vulnerability in women. Our study evolved in this exciting direction, however, when we realized that USP11 is located on the X chromosome and that even nondementia females show physiologically increased USP11 levels in the brain. Another exciting result was that the removal of ubiquitin from tau by USP11 creates the necessary space on tau to allow another modification to occur, called acetylation. Previous studies have shown that acetylated tau is more prone to aggregation and is increased in AD and after traumatic brain injury. In this study, we found that USP11 not only reduces tau elimination but also increases tau aggregation by increasing its acetylation.
5)What are the limitations of the study?
This study provides a significant explanation for the increased vulnerability of women to AD through increased tau aggregation in the brain. However, another major aspect of brain pathology in AD is amyloid plaques, which have also been shown to be more extensive in women than in men. We did not specifically study brain amyloid plaque pathology in our current study, and this could be another avenue for understanding why AD is more prevalent and aggressive in women than in men.
6)How might these findings be put to use? What could be the impact of this study?
Like all enzymes, USP11 can be pharmacologically inhibited by drugs. Our hope is that academic laboratories and the pharmaceutical industry will take this opportunity to develop drugs that specifically inhibit USP11 activity. This could also come in the form of screening whether any existing FDA-approved drugs might happen to unexpectedly inhibit USP11. Based on the results of our study, we predict that USP11-inhibiting drugs will protect women from developing the accelerated tau pathology that they exhibit relative to men.
7)What is your future plan for following up on this study? Where is this research heading next? What do you plan to do with this information?
In addition to looking for ways to develop a medicine based on our results, we are also studying how this process affects downstream aspects of tau pathology in the brain. For example, we know that tau pathology spreads from nerve cell to nerve cell through interconnected regions of the brain. We are currently studying whether the modifications on the tau protein made by USP11 alter, and perhaps accelerate, the spreading of pathological tau throughout the brain. We are also investigating the possible connection between brain amyloid plaques and USP11.
https://authors.elsevier.com/a/1fsU2L7PXipzg
【原创文章】BioArt原创文章，欢迎个人转发分享，未经允许禁止转载，所刊登的所有作品的著作权均为BioArt所拥有。BioArt保留所有法定权利，违者必究。
个人中心
我是园区
退出
