Combating deleterious phase transitions in neurodegenerative disease.
Combating deleterious phase transitions in neurodegenerative disease.
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DOI：
10.1016/j.bbamcr.2021.118984
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Shorter J
中科院分区：
文献类型：
--
作者：
Darling AL;Shorter J
蛋白质聚集是神经退行性疾病的标志。然而，诱导致病性聚集的机制尚不清楚。最近，人们发现，在神经退行性疾病中发现的几种处于聚集或错误定位状态的病理蛋白也能够在生理条件下进行液-液相分离。尽管这些相变对于各种生理功能很重要，但神经退行性疾病相关的突变和条件可以改变这些蛋白质的 LLPS 行为，从而引起毒性。因此，拮抗异常 LLPS 的疗法可能能够减轻神经退行性疾病中普遍存在的毒性和聚集。在这里，我们讨论异常蛋白质相变可能导致神经退行性疾病的机制。我们还概述了对抗有害阶段的潜在治疗策略。
Protein aggregation is a hallmark of neurodegenerative diseases. However, the mechanism that induces pathogenic aggregation is not well understood. Recently, it has emerged that several of the pathological proteins found in an aggregated or mislocalized state in neurodegenerative diseases are also able to undergo liquid-liquid phase separation under physiological conditions. Although these phase transitions are important for various physiological functions, neurodegenerative disease-related mutations and conditions can alter the LLPS behavior of these proteins, which can elicit toxicity. Therefore, therapeutics that antagonize aberrant LLPS may be able to mitigate toxicity and aggregation that is ubiquitous in neurodegenerative disease. Here, we discuss the mechanisms by which aberrant protein phase transitions may contribute to neurodegenerative disease. We also outline potential therapeutic strategies to counter deleterious phases.
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