PDF(Pubmed)
Abstract：
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.
摘要：
不溶性蛋白质沉积物是神经退行性疾病和痴呆的常见形式的标志。错误折叠蛋白的异常聚集涉及随着时间的推移而发生的一系列复杂的事件，从细胞到神经变性的临床阶段。通过增加的细胞应激和蛋白质稳态(蛋白质稳态)功能的丧失而使神经元健康下降与聚集体的积累相关。在细胞层面,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重要过程。研究骨料分解和降解的反向过程直到最近才获得动力，以下是具有不同聚集-分解活性的酶的报道。在这次审查中,我们将讨论泛素-蛋白酶体系统和解聚机制如VCP/p97和HSP70系统如何分解和/或降解蛋白质聚集体。除了它们的规范关联功能之外，这些酶似乎共享一个共同的特征:以LLPS驱动的方式可逆地组装成液滴。我们回顾了LLPS在通过局部增加液滴结构中这些酶及其共蛋白的浓度来增强聚集体的分解中的作用。我们建议这种活动可以通过解聚酶机械的一致行动来实现，泛素-蛋白酶体系统及其共蛋白，所有这些都凝聚在瞬态聚集体缔合液滴(TAAD)中，最终导致骨料清除。我们进一步推测，TAAD中这些酶活性的持续参与将不利于正常的细胞功能，需要这些活动的地方。促进TAAD中内源性解聚和降解活性的可能性可能代表了治疗性干预以恢复神经变性早期蛋白质稳态的新目标。
