蝙蝠侠或小丑: 磷脂酶遗传变异对阿尔茨海默病...
来源：倍可亲(backchina.com)
蝙蝠侠或小丑的杰作：磷脂酶 C-g2 遗传变异对阿尔茨海默病截然不同的影响
倍可亲科学专题 Lily
你一定很熟悉蝙蝠侠的电影吧，蝙蝠侠是英雄人物，小丑是坏蛋。 蝙蝠侠和他的超级英雄伙伴们志在拯救世界，而小丑呢，有时单独行动，有时联合其他超级恶棍，乐于毁灭哥谭市。通常电影在接近结尾时，蝙蝠侠和小丑会展开一场世纪决战，大战的结局总是蝙蝠侠胜出，而小丑锒铛入狱，在狱中，小丑恨恨地密谋卷土重来。电影情节往往跌宕起伏，让人百看不厌。不过现在，我们准备读一篇医学论文。那啥，你都开始打哈欠了！别介，这篇论文没那么枯燥，它就像一部蝙蝠侠电影！
论文中, 科研人员使用用小鼠模型来研究阿尔茨海默病。我们可以把小鼠的大脑当做是哥谭市，其大脑皮层是市中心，数十亿个神经元是城市中的主要居民，星形胶质细胞是城市维护人员，而小胶质细胞负责安全和风险管理。城市里储存着数以百万计的操作指南（基因），供市民和工作人员们一丝不苟、按部就班地工作。操作指南不太容易翻开，所以工作人员通常不直接阅读指南，而是看上面传达下来什么信息（RNA），决定应该做什么。由于城市年代久远，缺乏维护，β淀粉样蛋白开始到处堆积，这种蛋白难以分解和清除，实在让人头疼。还有另一种危险物质P-Tau，居然出现在运输系统中，让不同工作团队之间沟通困难。久而久之，哥谭市的居民越来越少（脑细胞死亡），城市规模也逐日缩小（脑萎缩）。
尽管面临这么多的挑战，小胶质细胞的团队仍在下不知疲倦地工作。他们的主要职责是监控城市中的潜在威胁，例如病毒或细菌的入侵，保护公民和城市基础设施免受攻击。他们还可以在城市受到攻击后，帮忙打扫残局，恢复正常秩序。小胶质细胞的团队常常使用一本重要操作指南，叫磷脂酶 C-g2 基因（PLCG2）。依据这本指南，他们可以制造出PLCγ2蛋白，PLCγ2蛋白在启动各种下游程序（信号通路）中几乎必不可缺。
蝙蝠侠监督着打印一些 PLCG2。真是人无完人，打印出了一点点小差错，产生了一个叫PLCG2P522R 的变体指南。但神奇的是，PLCG2P522R 指南在防止哥谭市恶化方面比原始版本更有效。与此同时，小丑也在监督PLCG2的打印，他犯了一个重大错误，结果生成了一本名为PLCG2M28L的邪恶指南。
由于哥谭市中β-淀粉样蛋白**成患，小胶质细胞团队接到了命令，务必清楚垃圾。糟糕，小胶质细胞团队使用了错误的指南PLCG2M28L！上级看似把行动的消息发送给了团队成员，但无论如何，根据指令，功能性 PLCγ2 蛋白就是造不出来。缺乏必要的启动物质，维护和清理工作根本就无法开展，结果城市中β-淀粉样斑块反而变得越来越多。意识到情况严重后，小胶质细胞团队决定通过表达促炎细胞因子来启动危机管理程序。此举是为了深度激发团队的潜力，更有效地完成清理任务。事实上，这种动员强度太大，时有误伤团队成员的风险。然而要命的是，危机管理行动也需要PLCγ2蛋白，现在PLCγ2蛋白缺失，危机管理行动同样也失败了（IL1B、TNF-α 和 IL4 等促炎细胞因子的表达都低于对照城市）。可怜的哥谭市，市中心β-淀粉样蛋白堆积如山，几近崩溃，PLCG2M28L小鼠记忆力也严重受损。相反地，使用蝙蝠侠的PLCG2P522R指南的团队，成绩斐然。他们应用PLCG2P522R指南制造了充足的PLCγ2蛋白，成功完成了维护和危机管理任务，并防止了β-淀粉样蛋白在市中心的进一步堆积。
事到如今，大家都知道是Joker 的邪恶指南 PLCG2M28L造成了行动失败。但具体是哪些环节出来了问题呢？调查局在市中心搞了一个彻底的调查，收集了市中心传达的所有信息，用批量 RNA 测序进行了仔细分析。看起来，小丑的PLCG2M28L指南严重扰乱了市中心的通讯路径（突触功能），并让工作人员对至少 593 份其他指南的阐释出现了异常，受到波及的指南范围很广，涵盖了危机管理（炎症反应）、垃圾清理和回收（吞噬/内吞作用）、人员招募和培训（胶质细胞发育）、城市维护和重建（脂肪酸生物合成）等重要方面。
大规模调查肯定不够精准，调查局于是又搞了一个针对小胶质细胞团队的调查。每个团队队员被单独问询，为了防止冤假错案，调查局用其他功能团队的人员，如神经元、星形胶质细胞、内皮细胞等作为对照。调查局扣押了被调查人员的计算机（细胞核），对从计算机发出的原始信息进行了单核 RNA测序。工作量简直惊人，总共要分析62,588 台计算机！通过分析，调查人员更加明确，只有小胶质细胞的团队受到了Joker的PLCG2M28L指南的不良影响。现在调查范围再度缩小，只用分析7909台计算机了，这些计算机来分别来自于使用原始版本PLCG2、蝙蝠侠版本PLCG2P522R、和小丑版本PLCG2M28L指南的小胶质细胞队员。调查局根据这些小胶质细胞队员对 三个版本指南的不同阐释，以及每人在危机期间的行为模式，认定他们属于 5 个不同的团伙。5个团伙无一例外，危急时刻全部表现失职，产生了严重的信息发送异常，并导致了现场人员调度（细胞迁移）失效，清除有害物质（细胞内吞）能力受损，和危机管理（炎症反应和细胞凋亡过程）失灵。最后，调查局给团伙成员都建立了个人档案，记录了他们的相互联络方式和响应模式，团伙成员的个人生物特征以及他们应对危机时参考的各种行动指南也被存档，以便于将来进一步的调查。
上述故事于2023年9月12日发表在著名医学期刊《免疫》上，标题为“Genetic variants of phospholipase C-g2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease”. (https://www.cell.com/action/showPdf?pii=S1074-7613%2823%2900364-3)。你也许有点不解，怎么没看到蝙蝠侠和小丑之间的史诗级对决？非常遗憾，这个故事中的蝙蝠侠和小丑穿梭于平行宇宙中的不同哥谭市，并未有过交集。在接下来的故事中，他们也许会在同一个城市见面。怎么个见面法呢？这个嘛，有可能蝙蝠侠变身为一只小公鼠，而小丑变身为一只小母鼠，他们喜结连理后，世纪决战就在他们的后代的大脑中打响。情节好曲折呵，难以想象！
Batman or Joker’s printing: Opposite Influences of Phospholipase C-g2 Genetic Variants in Alzheimer’s Disease
BackChina Science Lily
You might be very familiar with the Batman movies. Batman is the hero and Joker is the villain. Batman works together with other superheroes to save the world, whereas Joker, either works alone or with other supervillains, trying to destroy Gotham City. At the end of the movies, Batman and Joker usually have a decisive battle. Batman always smiles to the end, whereas Joker goes to jail and plots for his next revenge. Funny and exciting to watch? Absolutely! Now, it's time for us to read a medical paper. You might start to yawn, but come on! It’s not that boring, it is like a Batman movie!
In this tale (research), a mouse model was used to study Alzheimer’s disease and the mouse brain was Gotham City. Cortex was the city center. Billions of neurons were the main citizens. Astrocytes worked as the city maintenance crew and microglia responded for security and risk management. There were millions of guidebooks (genes) stored in the city for the citizens and workers to properly carry out their duties. Guidebooks are kind of difficult to open for reading, so people usually use messages (RNA) to direct what they should do, instead of using the guidebooks directly. Because the city was quite old and lacked maintenance, β-amyloid, a kind of garbage difficult to decompose and remove, started to pile everywhere. Another kind of dangerous material, P-Tau, also appeared in the transportation system, making communication between different teams difficult. Consequently, the city gradually lost its citizens (brain cells die), and the city size was shrinking significantly (cerebral atrophy).
The microglia team worked tirelessly in these challenging conditions. Their primary responsibility was to monitor potential threats, like viruses or bacteria circulating through the city, as well as damage and injuries to both citizens and the city's infrastructure. They also helped to clean the battlefield and repair damage. An important guidebook for the team is Phospholipase C-g2 gene (PLCG2). Using the guidebook, they could make the protein PLCγ2, which plays an indispensable role in kickstarting various downstream processes (signaling pathways).
Batman oversaw the production of PLCG2. However, as nobody is perfect, a minor error occurred during production, resulting in a variant known as PLCG2P522R. Interestingly, PLCG2P522R proved to be even more effective than the original version in preventing the deterioration of Gotham City. In contrast, Joker, while overseeing the production, a serious mistake was created, which was accompanied with a malevolent guidebook called PLCG2M28L.
As β-amyloid continued to accumulate in Gotham City, the microglia team received the order to take out the trash. Regrettably, the team relied on the faulty guidebook PLCG2M28L. Messages that appeared normal were sent to the team members, but they struggled to make functional PLCγ2 proteins based on the messages. Without the jump-starter, the maintenance and cleanup job cannot be initiated, and β-amyloid plaques formed even more in the city. Upon recognizing this ominous development, the microglia team decided to initiate crisis management by turning on proinflammatory cytokines expression. This was done to galvanize the team's efforts and accomplish the task more effectively. Given the intensity of the process, it sometimes could be risky for the team members themselves. Unfortunately, the jump-starter PLCγ2 was also required by the crisis management, and without it, the action also failed (proinflammatory cytokines including IL1B, TNF-α, and IL4 expression down-regulated in comparison to control brains). The poor Gotham City, burdened with heaps of β-amyloid at the city center, was facing the fate of collapse and the working memories of the PLCG2M28Lmice were severely impaired. Now, let's talk about Batman's guidebook. It won't let you down. By using PLCG2P522R, the microglia team made sufficient PLCγ2, successfully fulfilled the maintenance and the crisis management task, and prevented the β-amyloid building-up in the city center.
So far, it is common knowledge that Joker’s guidebook PLCG2M28Lwas the project’s downfall. But how? A thorough investigation was conducted throughout the city center and all the transmitted messages were scrutinized by using bulk RNA sequencing. It became evident that Joker’s guidebook severely disrupted the communication pathways of the city center (synaptic function) and led to the abnormal interpretation of at least 593 other guidebooks, encompassing critical subjects like crisis management (inflammatory response), cleanup and recycling (phagocytosis/endocytosis), personnel recruit and training (glial cell development), city maintenance and reconstruction (fatty acid biosynthesis).
To prevent inaccuracies from large-scale investigations, a more targeted investigation was conducted on individual microglia. Personnel from other functional teams, such as neurons, astrocytes, endothelia, were used as controls. Investigators analyzed the original going-out messages from the computers (nucleus) of the investigated subjects using Single-nuclei RNA-sequencing. This was a huge amount of work, in total, 62,588 computers were collected. Investigators further confirmed that only microglia’s team was under the bad influence of Joker’s PLCG2M28L. After comparing messages from 7909 typical computers collected from individual microglial guided by original PLCG2, PLCG2M28L, or PLCG2P522R, investigators identified 5 action clusters based on their varying interpretations of PLCG2M28Land their behaviors during the crisis. All five clusters faltered in their duties, resulting in abnormal message-sending, ineffective field operation (cell migration), impaired harm clearance (endocytosis), and compromised crisis management (inflammatory responses and apoptotic process). Following this, historical files were created for cluster members based on their responses to PLCG2, PLCG2M28L, or PLCG2P522R. Additionally, personal biological identities, as well as guidebooks they utilized during the crisis, were archived to facilitate future investigations.
The above story was published in the renowned medical journal Immunity on September 12, 2023, under the title “Genetic variants of phospholipase C-g2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease”. (https://www.cell.com/action/showPdf?pii=S1074-7613%2823%2900364-3). You might be wondering, where's the epic showdown between Batman and Joker? Regrettably, in this tale, Batman and Joker never crossed paths as they operated in different Gotham Cities in the parallel universe. In the upcoming story, they might find themselves in the same city. How? You may ask. Well, Batman will be a male mouse, and Joker a female mouse. After they tie the knot, the decisive battle could unfold within their offspring’s brains. What a twisted plot! Hard to imagine.
