Mee Hayes Emma, Sirvio Liina, Ye Yu
Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, United Kingdom.
UK Dementia Research Institute at Imperial College London, London, United Kingdom.
Front Aging Neurosci. 2022 Apr 6;14:854380. doi: 10.3389/fnagi.2022.854380. eCollection 2022.
Insoluble protein deposits are hallmarks of neurodegenerative disorders and common forms of dementia. The aberrant aggregation of misfolded proteins involves a complex cascade of events that occur over time, from the cellular to the clinical phase of neurodegeneration. Declining neuronal health through increased cell stress and loss of protein homeostasis (proteostasis) functions correlate with the accumulation of aggregates. On the cellular level, increasing evidence supports that misfolded proteins may undergo liquid-liquid phase separation (LLPS), which is emerging as an important process to drive protein aggregation. Studying the reverse process of aggregate disassembly and degradation has only recently gained momentum, following reports of enzymes with distinct aggregate-disassembly activities. In this review, we will discuss how the ubiquitin-proteasome system and disaggregation machineries such as VCP/p97 and HSP70 system may disassemble and/or degrade protein aggregates. In addition to their canonically associated functions, these enzymes appear to share a common feature: reversibly assembling into liquid droplets in an LLPS-driven manner. We review the role of LLPS in enhancing the disassembly of aggregates through locally increasing the concentration of these enzymes and their co-proteins together within droplet structures. We propose that such activity may be achieved through the concerted actions of disaggregase machineries, the ubiquitin-proteasome system and their co-proteins, all of which are condensed within transient aggregate-associated droplets (TAADs), ultimately resulting in aggregate clearance. We further speculate that sustained engagement of these enzymatic activities within TAADs will be detrimental to normal cellular functions, where these activities are required. The possibility of facilitating endogenous disaggregation and degradation activities within TAADs potentially represents a novel target for therapeutic intervention to restore protein homeostasis at the early stages of neurodegeneration.
不溶性蛋白质沉积物是神经退行性疾病和常见痴呆形式的标志。错误折叠蛋白质的异常聚集涉及一系列随着时间推移发生的复杂事件，从神经退行性变的细胞阶段到临床阶段。通过增加细胞应激和蛋白质稳态（蛋白质平衡）功能丧失导致神经元健康下降与聚集体的积累相关。在细胞水平上，越来越多的证据支持错误折叠的蛋白质可能经历液-液相分离（LLPS），这正在成为驱动蛋白质聚集的一个重要过程。随着具有独特聚集体拆解活性的酶的报道，研究聚集体拆解和降解的反向过程直到最近才获得动力。在这篇综述中，我们将讨论泛素-蛋白酶体系统以及诸如VCP/p97和HSP70系统等解聚机制如何拆解和/或降解蛋白质聚集体。除了它们典型的相关功能外，这些酶似乎有一个共同特征：以LLPS驱动的方式可逆地组装成液滴。我们综述了LLPS通过在液滴结构内局部增加这些酶及其共蛋白的浓度来增强聚集体拆解的作用。我们提出，这种活性可能是通过解聚酶机制、泛素-蛋白酶体系统及其共蛋白的协同作用来实现的，所有这些都浓缩在与聚集体相关的瞬时液滴（TAADs）中，最终导致聚集体清除。我们进一步推测，在TAADs中持续进行这些酶活性将对需要这些活性的正常细胞功能有害。促进TAADs内源性拆解和降解活性的可能性可能代表了在神经退行性变早期恢复蛋白质稳态的治疗干预的一个新靶点。
