Meisl Georg, Knowles Tuomas P J, Klenerman David
Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, United Kingdom.
Front Neurosci. 2022 Jun 30;16:909861. doi: 10.3389/fnins.2022.909861. eCollection 2022.
Through advances in the past decades, the central role of aberrant protein aggregation has been established in many neurodegenerative diseases. Crucially, however, the molecular mechanisms that underlie aggregate proliferation in the brains of affected individuals are still only poorly understood. Under controlled conditions, significant progress has been made in elucidating the molecular mechanisms that take place during the assembly of purified protein molecules, through advances in both experimental methods and the theories used to analyse the resulting data. The determination of the aggregation mechanism for a variety of proteins revealed the importance of intermediate oligomeric species and of the interactions with promotors and inhibitors. Such mechanistic insights, if they can be achieved in a disease-relevant system, provide invaluable information to guide the design of potential cures to these devastating disorders. However, as experimental systems approach the situation present in real disease, their complexity increases substantially. Timescales increase from hours an aggregation reaction takes , to decades over which the process takes place in disease, and length-scales increase to the dimension of a human brain. Thus, molecular level mechanistic studies, like those that successfully determined mechanisms , have only been applied in a handful of living systems to date. If their application can be extended to further systems, including patient data, they promise powerful new insights. Here we present a review of the existing strategies to gain mechanistic insights into the molecular steps driving protein aggregation and discuss the obstacles and potential paths to achieving their application in disease. First, we review the experimental approaches and analysis techniques that are used to establish the aggregation mechanisms and the insights that have been gained from them. We then discuss how these approaches must be modified and adapted to be applicable and review the existing works that have successfully applied mechanistic analysis of protein aggregation in living systems. Finally, we present a broad mechanistic classification of systems and discuss what will be required to further our understanding of aggregate formation in living systems.
在过去几十年里，异常蛋白质聚集在许多神经退行性疾病中的核心作用已得到确立。然而，至关重要的是，对于受影响个体大脑中聚集体增殖的分子机制，我们仍然知之甚少。在可控条件下，通过实验方法和用于分析所得数据的理论的进步，在阐明纯化蛋白质分子组装过程中发生的分子机制方面已经取得了重大进展。对多种蛋白质聚集机制的确定揭示了中间寡聚体物种以及与促进剂和抑制剂相互作用的重要性。如果能够在与疾病相关的系统中获得这种机制上的见解，将为指导这些毁灭性疾病潜在治疗方法的设计提供宝贵信息。然而，随着实验系统接近实际疾病中的情况，其复杂性大幅增加。时间尺度从聚集反应所需的数小时增加到疾病中该过程发生的数十年，长度尺度增加到人类大脑的维度。因此，像那些成功确定机制的分子水平机制研究，迄今为止仅应用于少数活体系统。如果它们的应用能够扩展到更多系统，包括患者数据，有望带来强大的新见解。在这里，我们对现有的获取驱动蛋白质聚集分子步骤机制见解的策略进行综述，并讨论在疾病中实现其应用的障碍和潜在途径。首先，我们回顾用于建立聚集机制的实验方法和分析技术以及从中获得的见解。然后，我们讨论这些方法必须如何修改和调整才能适用，并综述已成功将蛋白质聚集机制分析应用于活体系统的现有工作。最后，我们对系统进行广泛的机制分类，并讨论进一步理解活体系统中聚集体形成需要什么。
