Biological Amyloid Aggregation as a Post-Translational Regulatory Pathway

在正常的环境条件下，生物分子执行维持人类细胞所必需的基本任务。然而，暴露在恶劣和应激的条件下，如高温、酸度和紫外线辐射，会扰乱这些生物分子的功能，损害细胞成分。这需要激活修复途径，试图补偿环境应激源的有害影响。这些细胞对抗措施的成功或失败最终决定了一个细胞和/或生物体能否在暴露中存活下来。最近，我们发现了一种新的生物途径，可以在细胞应激期间提高存活率。通过可逆形成致密的、不可溶的和纤维状的蛋白质块(称为淀粉样蛋白)，细胞可以迅速关闭非必要的功能，专注于修复受损的成分。这些生物淀粉样蛋白特别令人惊讶的是，它们与神经系统疾病(如阿尔茨海默氏症、帕金森氏症和疯牛病)患者中发现的有毒斑块非常相似。这表明，这一自然途径可能是与疾病相关的斑块的生物对应的第一批例子之一。这项研究计划的目的是增进我们对这一新发现的生物现象的了解。天然淀粉样蛋白聚集体是如何形成和分解的，是什么环境应激源激活了这一过程，以及为什么它对细胞具有保护作用，这些都是我们希望解决的长期问题。具体来说，今后5年，我们将重点抓好以下三个方面的工作。 目的I：研究一个鲜为人知的生物分子家族(非编码RNA)在蛋白质簇形成中的重要作用。在这里，我们将确定环境信号如何激活这些非编码RNA，以及这些活性分子如何将蛋白质转化为淀粉样聚集体。 目的II：寻找触发淀粉样蛋白形成的新环境应激源。这将帮助我们了解细胞/生物利用这一新的应激反应途径的频率。 目的III：确定形成应激特异性淀粉样蛋白聚集体的蛋白质。这是一个重要的问题，因为它帮助我们了解细胞如何适应不同的环境(即高温和低pH)，结果将使我们更好地了解提高生存的细胞途径。 总体而言，这项工作对基础科学社区(RNA、结构和细胞生物学)以及翻译研究人员都很重要，他们可以利用我们对淀粉样蛋白自然形成的洞察力来产生新的治疗途径，从而帮助治疗影响加拿大老龄化人口的神经疾病。

Under normal environmental situations, biological molecules perform the basic tasks necessary to maintain human cells. However, exposure to harsh and stressful conditions, such as high temperature, acidity, and UV radiation, can disrupt the function of these biological molecules and damage cellular components. This requires the activation of repair pathways, which attempt to compensate for the harmful effects of an environmental stressor. The success or failure of these cellular countermeasures ultimately determines whether a cell and/or organism survives exposure. Recently, we identified a new biological pathway that enhances survival during periods of cellular stress. Through the reversible formation of dense, insoluble, and fibrous protein clumps (termed amyloids) a cell can rapidly shut down non-essential functions, to focus on repairing the damaged components. What is particularly striking about these biological amyloids is their close resemblance to the toxic plaques found in patients with neurological disorders (such as Alzheimer's, Parkinson's and mad cow diseases). This suggests that this natural pathway may be one of the first examples of a biological counterpart to the disease-associated plaques. The goal of this research program is to enhance our understanding of this newly discovered biological phenomenon. How natural amyloid aggregates form and disassemble, what environmental stressors activate this process, and why it is protective to the cell are long-term questions that we hope to address. Specifically in the next 5 years, we will focus our efforts on the following three aims. Aim I: Examine the essential role of a poorly understood family of biological molecules (noncoding RNA) in the formation of protein clumps. Here, we will identify how environmental signals activate these noncoding RNAs and how these active molecules convert proteins into amyloid aggregates. Aim II: Find new environmental stressors that trigger amyloid formation. This will help us understand how often cells/organisms utilize this novel stress-response pathway. Aim III: Identify the proteins that form stress-specific amyloid aggregates. This is an important question, as it helps us understand how cells adapt to different situations (i.e., high temperature versus low pH), and the results will give us a better understanding of cellular pathways that enhance survival. Overall, this work will be important to basic scientific communities (RNA, structural, and cellular biology), as well as translational researchers who could use our insight into the natural formation of amyloids to generate new therapeutic avenues that could help treat neurological diseases affecting Canada's aging population.