Lyterian Therapeutics, Inc.

神经退行性疾病，是一类由神经细胞的退行性损害导致神经系统功能逐渐丧失的疾病，包括阿尔茨海默病、帕金森病、亨廷顿症、渐冻症等。需要注意的是，神经退行性疾病目前尚无根治方法，现有疗法主要是减轻症状和延缓疾病进程。许多神经退行性疾病，例如阿尔茨海默病、帕金森病，其特征是蛋白质团块在大脑中积聚，这些蛋白质聚集物会杀死脑细胞，从而损害神经系统的正常功能。然而，虽然科学家们一直致力于开发分解和清除这些蛋白质聚集物的疗法，但收效甚微。近日，加州大学伯克利分校的研究人员在 Nature 期刊发表题为：Stress response silencing by an E3 ligase mutated in neurodegeneration 的研究论文。这项研究表明，蛋白质聚集物的积累并不是杀死脑细胞的直接原因，过度的应激反应才是导致脑细胞死亡的罪魁祸首，这是一种应激后的“自杀行为”。该研究进一步提出，迫使应激反应停止的药物可以在无需清除大脑中蛋白质聚集物的情况下挽救神经退行性疾病的脑细胞，这为神经退行性疾病的治疗开辟了新的道路。人体内所有的细胞都生存在一种动态环境中，它们可能会暴露于温度波动、病毒、毒素或营养限制之下，到那时，细胞会启动一种被称为应激反应的保守信号通路，从而在这些不利条件下存活下来。短暂的应激反应可以帮助细胞度过难关，但长时间的应激反应却会造成致命的后果——触发细胞凋亡程序，促使细胞死亡。然而，当细胞在衰老或疾病中面临持续的应激反应时，可能会诱导不必要的细胞死亡，损害组织完整性，对机体健康造成不可逆的破坏性后果。早在2017年，该论文通讯作者 Michael Rapé 教授发现一种名为UBR4的E3泛素连接酶可以招募特定的泛素化信号，这种信号是消除细胞内蛋白质聚集体所必需的。直到后来，其他研究在某些神经退行性疾病患者中发现了UBR4的突变，才将UBR4与神经退行性疾病联系起来。在这项发表于 Nature 的最新研究中，研究团队进一步发现了一种被称为综合应激反应沉默因子（SIFI）的超大分子量蛋白质复合物。这台蛋白质机器有两种功能——清理聚集的蛋白质团块，然后关闭蛋白质团块引发的应激反应。有意思的是，UBR4实际上正是SIFI复合物的一部分。E3连接酶SIFI在线粒体输入应激时保护细胞SIFI复合物的核心底物是两种蛋白质——DELE1和HRI。DELE1可以感知线粒体定位的蛋白质的聚集，当它检测到有问题时，就会激活激酶HRI，启动应激反应——关闭大多数新蛋白质的合成，从而给细胞争取时间来解决这一问题，例如将这些聚集的蛋白质运输到正确位置或将其降解。在另一方面，SIFI复合物可以识别一个短的蛋白质片段，该片段充当一种邮政编码，允许蛋白质或蛋白质前体进入线粒体。当含有该片段的蛋白质在细胞质中积聚时，SIFI复合物就识别并降解它们。有趣的是，DELE1和HRI也通过SIFI机制进行降解，防止应激反应的过度激活。SIFI的核心底物是DELE1和HRI因此，在正常情况下，当线粒体定位的蛋白质在细胞质中异常积累时，SIFI会短暂激活其控制的应激反应来处理这一细胞内问题。然而，如果SIFI的某些组分发生突变，例如UBR4缺失，SIFI无法快速降解DELE1和HRI，细胞就会经历长期性的应激反应，最终导致细胞死亡。打个形象的比喻，这就像是打扫干净房子再睡觉一样，你不仅需要打扫房间，还需要在睡觉前关灯。如果你直接关灯，那么就没办法清扫垃圾；如果你打扫完不关灯，你也难以入睡。在某种情况下，如果你缺少打扫工具、垃圾太多或者开关坏了，你都无法入睡，最终被“活活累死”。SIFI沉默线粒体应激反应回归正题，对于细胞来说也是如此。SIFI复合物总是试图先收拾烂摊子，因此它不能关灯，只要细胞中仍有一个蛋白质团块，灯总是亮着的。然而，如果灯一直亮着——即持续性应激反应，细胞就会死亡。换而言之，在神经退行性疾病中，大量积累的蛋白质团块劫持了SIFI复合物介导的应激反应的沉默机制，通过干扰它使其彻底停摆，进而诱导持续性应激反应，最终导致神经细胞大量死亡，损害大脑正常功能。SIFI靶向降解异常聚集的线粒体蛋白从这一点来看，如果能有一种药物可以直接关闭应激反应，是否就能拯救脑细胞从根本上治疗神经退行性疾病呢？2013年，加州大学旧金山分校的研究人员发现了一种名为ISRIB的药物，可以作为应激反应的抑制剂，并已经被证明可以改善小鼠的记忆力，减少与年龄相关的认知能力下降。此外，在神经退行性疾病小鼠模型中，即使不清除聚集的蛋白质团块，仅仅通过药物沉默应激反应也能促进神经细胞存活。这一发现强调了应激反应信号终止的重要性，意味着可以通过控制应激反应来治疗广泛的神经退行性疾病。SIFI调节应激反应沉默的模式图Michael Rapé教授表示，在过去，科学家们一致认为普遍存在于神经退行性疾病患者大脑中的蛋白质聚集体会直接杀死神经细胞，例如，通过刺穿这些细胞内的膜结构。然而，这项最新研究表明，蛋白质聚集体抑制应激反应的沉默过程，使得应激反应一直在进行，而后者才是杀死脑细胞的根本原因。Michael Rapé 教授已经是两家初创公司 Nurix Therapeutics 和 Lyterian Therapeutics 的联合创始人，他正在致力于寻找一种新疗法，可以在关闭应激反应的同时，保持细胞对蛋白质聚集体的清理，进而用于治疗神经退行性疾病。论文链接：https://www.nature.com/articles/s41586-023-06985-7封面图来源：pixabay版权声明/免责声明个本文为授权转载文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CCO协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢!药时代官方网站:www.drugtimes.cn联系方式:电话:13651980212微信:27674131邮箱:contact@drugtimes.cn想要加速审批上市的药物退市分几步？高管被捕、试验失败、自愿撤市、专家咨询委员会反对……传奇Carvykti获批二线适应症在即！Claudin 18.2：被FDA拒批的“第一”和来势汹汹的竞争者们点击这里，欣赏更多精彩内容！

Many neurodegenerative diseases, such as dementia, are characterized by the abnormal aggregation of proteins inside cells, and treatments are being developed to break them up. But new research suggests that for some diseases, the aggregates are not directly killing cells. Aggregates prevent a protein, SIFI, from switching off the cells' stress response, and the constant stress kills cells. This suggests a strategy to treat these diseases without needing to mop up protein aggregates. Many neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, are characterized by the accumulation of protein clumps, or aggregates, in the brain, which has led scientists to assume that the protein tangles kill brain cells. The search for treatments that break up and remove these tangled proteins has had little success, however. But a new discovery by University of California, Berkeley, researchers suggests that the accumulation of aggregated proteins isn't what kills brain cells. Rather, it's the body's failure to turn off these cells' stress response. In a study published online Jan. 31 in the journal Nature, the researchers reported that delivering a drug that forces the stress response to shut down saves cells that mimic a type of neurodegenerative disease known as early-onset dementia. According to lead researcher Michael Rapé, the finding could offer clinicians another option for treatment for some neurodegenerative diseases, at least for those caused by mutations in the protein that switches off the cellular stress response. These include inherited diseases that lead to ataxia, or loss of muscle control, and early-onset dementia. In addition, Rapé noted that other neurodegenerative diseases, including Mohr-Tranebjærg syndrome, childhood ataxia and Leigh syndrome, are also characterized by stress responses in overdrive and have symptoms similar to those of the early onset dementia mimicked in the new study. "We always thought that protein clumps directly kill neurons, for example by puncturing membrane structures within these cells. Yet, we now found that aggregates prevent silencing of a stress response that cells originally mount to cope with bad proteins. The stress response is always on, and that's what kills the cells," said Rapé, head of the new division of molecular therapeutics in UC Berkeley's Department of Molecular and Cell Biology and a Howard Hughes Medical Institute investigator. "We think that the same mechanisms may underlie more common pathologies that also show widespread aggregation, such as Alzheimer's disease or frontotemporal dementia, but more work is needed to investigate the role of stress signaling in these diseases." Key to the discoveries by Rapé's lab was the researchers' finding that stress responses need to be turned off once a brain cell has successfully addressed a difficult situation. Rapé explained this finding to his son in simple terms: You not only need to clean up your room, but also turn out the light before going to bed. If you don't turn off the light, you can't fall asleep, but if you turn it off before you cleaned up your room, you would stumble if you had to get up in the dark. Similarly, a cell has to clean up protein aggregates before turning off the stress response. If it doesn't turn off the stress response, the cell will ultimately die. "Aggregates don't kill cells directly. They kill cells because they keep the light on," he said. "But that means that you can treat these diseases, or at least the dozen or so neurodegenerative diseases that we found have kept their stress responses on. You treat them with an inhibitor that turns off the light. You don't have to worry about completely getting rid of large aggregates, which changes how we think about treating neurodegenerative diseases. And most importantly, it makes this really doable." In their paper, Rapé and his colleagues describe a very large protein complex they discovered and called SIFI (SIlencing Factor of the Integrated stress response). This machine serves two purposes: It cleans up aggregates and, afterward, turns off the stress response triggered by the aggregated proteins. The stress response controlled by SIFI is switched on to deal with specific intracellular problems -- the abnormal accumulation of proteins that end up at the wrong location in the cell. If components of SIFI are mutated, the cell will accumulate protein clumps and experience an active stress response. But it is the stress response signaling that kills the cells. "The SIFI complex would normally clear out the aggregating proteins. When there are aggregates around, SIFI is diverted from the stress response, and the signaling continues. When aggregates have been cleared -- the room has been cleaned up before bedtime -- then the SIFI is not diverted away anymore, and it can turn off the stress response," he said. "Aggregates kind of hijack that natural stress response-silencing mechanism, interfere with it, stall it. And so that's why silencing never happens when you have aggregates, and that's why cells die." A future treatment, Rapé said, would likely involve administration of a drug to turn off the stress response and a drug to keep SIFI turned on to clean up the aggregate mess. Ubiquitin Rapé, who is also the Dr. K. Peter Hirth Chair of Cancer Biology, studies the role of ubiquitin -- a ubiquitous protein in the body that targets proteins for degradation -- in regulating normal and disease processes in humans. In 2017, he discovered that a protein called UBR4 assembles a specific ubiquitin signal that was required for the elimination of proteins that tend to aggregate inside cells. Only later did other researchers find that mutations in UBR4 are found in some inherited types of neurodegeneration. This discovery led Rapé to team up with colleagues at Stanford University to find out how UBR4 causes these diseases. "This was a unique opportunity: We had an enzyme that makes an anti-aggregation signal, and when it's mutated, it causes aggregation disease," he said. "You put these two things together and you can say, 'If you figure out how this UBR4 allows sustained cell survival, that probably tells you how aggregates kill cells.'" They found that UBR4 is actually part of a much larger protein complex, which Rapé dubbed SIFI, and they found that this SIFI machinery was needed when a cell couldn't sort proteins into its mitochondria. Such proteins that end up at the wrong location in cells tend to clump and, in turn, cause neurodegeneration. "Surprisingly, though, we found that the core substrates of the SIFI complex were two proteins, one of which senses when proteins don't make it into mitochondria. That protein detects that something is wrong, and it then activates a kinase that shuts down most of new protein synthesis as part of a stress response, giving the cell time to correct its problem with bringing proteins to the right location," he said. This kinase is also degraded through SIFI. A kinase is an enzyme that adds a phosphate group to another molecule, in this case a protein, to regulate important activities in the cell. By helping degrade these two proteins, the SIFI complex turns off the stress response that is caused by clumpy proteins accumulating at the wrong location. "That's the very first time that we've seen a stress response turned off in an active manner by an enzyme -- SIFI -- that happens to be mutated in neurodegeneration," Rapé said. While investigating how SIFI can turn off the stress response at the right time -- only after the room had been cleaned up -- the researchers found that SIFI recognizes a short protein segment that acts as a kind of ZIP code that allows proteins or protein precursors to get into the mitochondria, where they are processed. When they are prevented from getting in, they accumulate in the cytoplasm, but SIFI homes in on that ZIP code to eliminate them. The ZIP code looks just like the light switch. "When you have aggregates accumulating in the cytoplasm, now the ZIP code is still in the cytoplasm, and there's a lot of it there," he said. "And it's the same signal as you would have in the proteins that you want to turn off. So it basically diverts the SIFI complex from the light switch back to the mess. SIFI tries to clean up the mess first, and it cannot turn off the light. And so when you have an aggregate in the cell, the light is always on. And if the light is always on, if stress signaling is always on, the cell will die. And that's a problem." Rapé suspects that many intracellular protein aggregates characteristic of neurodegenerative diseases have similar consequences and may prevent the cell from switching off the stress response. If so, the fact that a drug can turn off the response and rescue brain cells bodes well for the development of treatments for potentially many neurodegenerative diseases. Already, another stress response inhibitor, a drug called ISRIB discovered at UCSF in 2013, has been shown to improve memory in mice and reduce age-related cognitive decline. "That means there is the prospect that by manipulating stress silencing, by turning off the light with chemicals, you might target other neurodegenerative diseases, as well," he said. "At the very least, it's another way we could help patients with these diseases. In the best possible way, I think it will change how we treat neurodegenerative diseases. That's why this is a really important story, why I think it's very exciting." Rapé, already a co-founder of two startups, Nurix Therapeutics Inc., and Lyterian Therapeutics, is now looking to develop therapies to silence the stress response while maintaining the cell's cleanup of protein aggregates. Co-authors with Rapé are postdoctoral fellows Diane Haakonsen, Michael Heider and Samuel Witus and graduate student Andrew Ingersoll, all of UC Berkeley, and Kayla Vodehnal, Takeshi Uenaka and Marius Wernig of Stanford. The work was supported primarily by the Stinehart-Reed Foundation and the National Institutes of Health (RF1 AG048131, T32MH020016-25).