Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors.
Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors.
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DOI：
10.3390/biology11071009
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发表时间：
2022-07-04
期刊：
影响因子：
4.2
通讯作者：
Guo, Lin
中科院分区：
文献类型：
--
作者：
Girdhar, Amandeep;Guo, Lin
异常的蛋白质相变和聚集引发各种神经退行性疾病，包括ALS、FTD、阿尔茨海默病和亨廷顿病。蛋白质和RNA在细胞核和细胞质之间的动态交换对于细胞功能是必不可少的，这在很大程度上受到不同RNA结合蛋白（RBP）（如FUS，TDP-43和hnRNPA 1/A2）在其各自的神经退行性疾病中的错误定位，相分离和聚集的影响。这些RBP的疾病相关异常积累通过破坏核膜结构和错误定位必需的NCT因子（如核孔蛋白、输入蛋白、输出蛋白和Ran蛋白及其调节组分）来损害核质转运（NCT）。核输入受体（nuclear import receptors，NIRs）通过调节输入/输出途径，具有修复RBP异常定位错误的潜力。近红外光谱还可以潜在地防止或逆转RBPs的相分离和纤维化。总体而言，这篇评论的重点是核输入受体在调节神经退行性疾病的相变的作用。具有低复杂性朊病毒样结构域（PLD）的RNA结合蛋白（RBP）可经历异常相变，并与神经退行性疾病如ALS和FTD有关。在疾病条件下，几种核RBP错误定位于细胞质内含物。核质转运受损是衰老和神经退行性疾病中观察到的另一个主要事件。核输入受体（nuclear import receptor，NIR）通过恢复其核定位来调节携带核定位信号的不同RBP的核质转运。NIR还可以特异性地溶解或防止野生型或疾病相关突变体RBP的聚集和液-液相分离，这是由于它们的伴侣活性。本文综述了内在无序蛋白的LLPS和近红外光谱在神经退行性变中调节LLPS的作用。本文还讨论了近红外光谱作为治疗剂在神经退行性疾病的影响。
Aberrant protein phase transitions and aggregation trigger various neurodegenerative diseases, including ALS, FTD, Alzheimer’s disease, and Huntington’s disease. Dynamic exchange of proteins and RNA between the nucleus and cytoplasm is essential for cellular functioning, which is greatly affected by the mislocalization, phase separation, and aggregation of different RNA-binding proteins (RBPs), such as FUS, TDP-43, and hnRNPA1/A2 in their respective neurodegenerative diseases. Disease-linked abnormal accumulation of these RBPs impairs the nucleocytoplasmic transport (NCT) by disrupting the nuclear envelope architecture and mislocalizing essential NCT factors, such as nucleoporins, importins, exportins, and the Ran protein and its regulatory components. Nuclear import receptors (NIRs) have the potential to restore abnormal mislocalization of RBPs by regulating the import/export pathway. NIRs can also potentially prevent or reverse the phase separation and fibrillization of RBPs. Overall, this review focuses on the role of nuclear import receptors in regulating phase transitions in neurodegenerative diseases. RNA-binding proteins (RBPs) with a low-complexity prion-like domain (PLD) can undergo aberrant phase transitions and have been implicated in neurodegenerative diseases such as ALS and FTD. Several nuclear RBPs mislocalize to cytoplasmic inclusions in disease conditions. Impairment in nucleocytoplasmic transport is another major event observed in ageing and in neurodegenerative disorders. Nuclear import receptors (NIRs) regulate the nucleocytoplasmic transport of different RBPs bearing a nuclear localization signal by restoring their nuclear localization. NIRs can also specifically dissolve or prevent the aggregation and liquid–liquid phase separation of wild-type or disease-linked mutant RBPs, due to their chaperoning activity. This review focuses on the LLPS of intrinsically disordered proteins and the role of NIRs in regulating LLPS in neurodegeneration. This review also discusses the implication of NIRs as therapeutic agents in neurogenerative diseases.
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影响因子：
14.8
作者：
Barmada, Sami J.;Serio, Andrea;Arjun, Arpana;Bilican, Bilada;Daub, Aaron;Ando, D. Michael;Tsvetkov, Andrey;Pleiss, Michael;Li, Xingli;Peisach, Daniel;Shaw, Christopher;Chandran, Siddharthan;Finkbeiner, Steven
通讯作者：
Finkbeiner, Steven
影响因子：
16.6
作者：
Ambadipudi S;Biernat J;Riedel D;Mandelkow E;Zweckstetter M
通讯作者：
Zweckstetter M
影响因子：
3.4
作者：
Azaldegui, Christopher A.;Vecchiarelli, Anthony G.;Biteen, Julie S.
通讯作者：
Biteen, Julie S.
影响因子：
5
作者：
Carey JL;Guo L
通讯作者：
Guo L
DOI：
10.1083/jcb.109.3.955
发表时间：
1989-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Akey CW
通讯作者：
Akey CW