Leaderless secretory proteins of the neurodegenerative diseases via TNTs: a structure-function perspective.
Leaderless secretory proteins of the neurodegenerative diseases via TNTs: a structure-function perspective.
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DOI：
10.3389/fnmol.2023.983108
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发表时间：
2023
影响因子：
4.8
通讯作者：
Manjithaya, Ravi
中科院分区：
文献类型：
--
作者：
Padmanabhan, Sreedevi;Manjithaya, Ravi
关键词：
神经退行性疾病引起的蛋白质，如α -突触核蛋白、tau蛋白和亨廷顿蛋白，已知通过外泌体、细胞外囊泡和隧道纳米管（tnt）穿越细胞。外泌体和tnt在细胞间通讯中似乎有很好的协同作用。有趣的是，许多已知的主要神经退行性蛋白/蛋白水解产物是无领导的，并且据报道也通过非常规的蛋白质分泌分泌出细胞。这些类包含内在无序的蛋白质和区域（idr）。这些蛋白质的动态行为是由于它们的异质构象，这是由于细胞内发生的各种因素所表现出来的。氨基酸序列及其化学修饰对idr在细胞内的功能作用有影响。形成聚集体导致神经变性的蛋白质在自噬和蛋白酶体系统过程中变得抵抗降解，从而导致隧道纳米管，TNT形成。穿越tnt的蛋白质可能依赖于也可能不依赖于自噬机制。目前尚不清楚这种蛋白质的构象是否在其从一个细胞转移到另一个细胞而不被降解的过程中起着至关重要的作用。虽然有一些实验数据，但仍有许多灰色地带需要重新审视。这篇综述提供了一个不同的角度来研究这些在细胞外分泌的无领导蛋白的结构和功能方面。在这篇综述中，注意力集中在导致无领导分泌蛋白聚集的特征上（从结构和功能方面），特别强调了tnt。
Neurodegenerative disease-causing proteins such as alpha-synuclein, tau, and huntingtin are known to traverse across cells via exosomes, extracellular vesicles and tunneling nanotubes (TNTs). There seems to be good synergy between exosomes and TNTs in intercellular communication. Interestingly, many of the known major neurodegenerative proteins/proteolytic products are leaderless and are also reported to be secreted out of the cell via unconventional protein secretion. Such classes contain intrinsically disordered proteins and regions (IDRs) within them. The dynamic behavior of these proteins is due to their heterogenic conformations that is exhibited owing to various factors that occur inside the cells. The amino acid sequence along with the chemical modifications has implications on the functional roles of IDRs inside the cells. Proteins that form aggregates resulting in neurodegeneration become resistant to degradation by the processes of autophagy and proteasome system thus leading to Tunneling nanotubes, TNT formation. The proteins that traverse across TNTs may or may not be dependent on the autophagy machinery. It is not yet clear whether the conformation of the protein plays a crucial role in its transport from one cell to another without getting degraded. Although there is some experimental data, there are many grey areas which need to be revisited. This review provides a different perspective on the structural and functional aspects of these leaderless proteins that get secreted outside the cell. In this review, attention has been focused on the characteristic features that lead to aggregation of leaderless secretory proteins (from structural-functional aspect) with special emphasis on TNTs.
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