The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration.
The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration.
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DOI：
10.1111/acel.12359
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发表时间：
2015-10
期刊：
影响因子：
7.8
通讯作者：
Kayed R
中科院分区：
文献类型：
--
作者：
Deger JM;Gerson JE;Kayed R
各种神经退行性疾病的特点是淀粉样蛋白如tau、α-突触核蛋白和淀粉样蛋白-β的积累。在这些稳定聚集体形成之前，相应的蛋白质的中间物种-寡聚物-出现。最近获得的数据表明，低聚物可能对阿尔茨海默病和帕金森病等神经退行性疾病具有最大的毒性和病理学意义。这些低聚物的共价修饰可能对疾病的生物过程至关重要。泛素和小泛素样修饰剂是常用的降解标记。虽然通过泛素化修饰大型淀粉样蛋白聚集体已经很好地建立起来，但对于泛素在低聚物加工中可能发挥的作用以及最近发现的泛素化的重要性知之甚少。许多与神经退行性变有关的蛋白质已被发现被聚合，尤其是阿尔茨海默氏症患者大脑中的tau蛋白。这一证据表明，虽然细胞识别危险蛋白质可能没有困难，但在患有神经退行性疾病的大脑中，蛋白酶体可能无法正确消化标记的蛋白质。这将允许毒性聚集体的发展，导致更多的蛋白酶体损伤，形成雪球效应，这可以解释大多数神经退行性疾病的指数发展。更好地了解低聚物的共价修饰可能对神经退行性疾病治疗方法的发展产生巨大影响。本文将重点介绍共价修饰诱导的tau蛋白和其他淀粉样蛋白的蛋白水解，以及最近发现的tau低聚物与sumo化之间的关系。
Various neurodegenerative diseases are characterized by the accumulation of amyloidogenic proteins such as tau, α-synuclein, and amyloid-β. Prior to the formation of these stable aggregates, intermediate species of the respective proteins—oligomers—appear. Recently acquired data have shown that oligomers may be the most toxic and pathologically significant to neurodegenerative diseases such as Alzheimer’s and Parkinson’s. The covalent modification of these oligomers may be critically important for biological processes in disease. Ubiquitin and small ubiquitin-like modifiers are the commonly used tags for degradation. While the modification of large amyloid aggregates by ubiquitination is well established, very little is known about the role ubiquitin may play in oligomer processing and the importance of the more recently discovered sumoylation. Many proteins involved in neurodegeneration have been found to be sumoylated, notably tau protein in brains afflicted with Alzheimer’s. This evidence suggests that while the cell may not have difficulty recognizing dangerous proteins, in brains afflicted with neurodegenerative disease, the proteasome may be unable to properly digest the tagged proteins. This would allow toxic aggregates to develop, leading to even more proteasome impairment in a snowball effect that could explain the exponential progression in most neurodegenerative diseases. A better understanding of the covalent modifications of oligomers could have a huge impact on the development of therapeutics for neurodegenerative diseases. This review will focus on the proteolysis of tau and other amyloidogenic proteins induced by covalent modification, and recent findings suggesting a relationship between tau oligomers and sumoylation.