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Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors

SIMPLE SUMMARY: 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 gre...

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Autores principales: Girdhar, Amandeep, Guo, Lin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311884/
https://www.ncbi.nlm.nih.gov/pubmed/36101390
http://dx.doi.org/10.3390/biology11071009
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author Girdhar, Amandeep
Guo, Lin
author_facet Girdhar, Amandeep
Guo, Lin
author_sort Girdhar, Amandeep
collection PubMed
description SIMPLE SUMMARY: 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. ABSTRACT: 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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spelling pubmed-93118842022-07-26 Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors Girdhar, Amandeep Guo, Lin Biology (Basel) Review SIMPLE SUMMARY: 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. ABSTRACT: 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. MDPI 2022-07-04 /pmc/articles/PMC9311884/ /pubmed/36101390 http://dx.doi.org/10.3390/biology11071009 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Girdhar, Amandeep
Guo, Lin
Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors
title Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors
title_full Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors
title_fullStr Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors
title_full_unstemmed Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors
title_short Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors
title_sort regulating phase transition in neurodegenerative diseases by nuclear import receptors
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311884/
https://www.ncbi.nlm.nih.gov/pubmed/36101390
http://dx.doi.org/10.3390/biology11071009
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