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Perturbations in Traffic: Aberrant Nucleocytoplasmic Transport at the Heart of Neurodegeneration

Neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington’s disease (HD), are characterized by intracellular aggregation of proteins. In the case of ALS and FTD, these protein aggregates are found in the cytoplasm of affected neurons and c...

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Autores principales: Fahrenkrog, Birthe, Harel, Amnon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316434/
https://www.ncbi.nlm.nih.gov/pubmed/30486313
http://dx.doi.org/10.3390/cells7120232
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author Fahrenkrog, Birthe
Harel, Amnon
author_facet Fahrenkrog, Birthe
Harel, Amnon
author_sort Fahrenkrog, Birthe
collection PubMed
description Neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington’s disease (HD), are characterized by intracellular aggregation of proteins. In the case of ALS and FTD, these protein aggregates are found in the cytoplasm of affected neurons and contain certain RNA-binding proteins (RBPs), namely the TAR DNA-binding protein of 43 kDa (TDP-43) and the fused in sarcoma (FUS) gene product. TDP-43 and FUS are nuclear proteins and their displacement to the cytoplasm is thought to be adverse in at least two ways: loss-of-function in the nucleus and gain-of-toxicity in the cytoplasm. In the case of HD, expansion of a polyglutamine (polyQ) stretch within the N-terminal domain of the Huntingtin (HTT) protein leads to nuclear accumulation of polyQ HTT (or mHTT) and a toxic gain-of-function phenotype resulting in neurodegeneration. Numerous studies in recent years have provided evidence that defects in nucleocytoplasmic transport critically contribute to the pathology of these neurodegenerative diseases. A new mechanistic view is emerging, implicating three types of perturbations in normal cellular pathways that rely on nucleocytoplasmic transport: displacement of nuclear transport receptors and nucleoporins from nuclear pore complexes (NPCs), mislocalization and aggregation of RNA-binding proteins, and weakening of the chaperone activity of nuclear import receptors.
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spelling pubmed-63164342019-01-09 Perturbations in Traffic: Aberrant Nucleocytoplasmic Transport at the Heart of Neurodegeneration Fahrenkrog, Birthe Harel, Amnon Cells Commentary Neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington’s disease (HD), are characterized by intracellular aggregation of proteins. In the case of ALS and FTD, these protein aggregates are found in the cytoplasm of affected neurons and contain certain RNA-binding proteins (RBPs), namely the TAR DNA-binding protein of 43 kDa (TDP-43) and the fused in sarcoma (FUS) gene product. TDP-43 and FUS are nuclear proteins and their displacement to the cytoplasm is thought to be adverse in at least two ways: loss-of-function in the nucleus and gain-of-toxicity in the cytoplasm. In the case of HD, expansion of a polyglutamine (polyQ) stretch within the N-terminal domain of the Huntingtin (HTT) protein leads to nuclear accumulation of polyQ HTT (or mHTT) and a toxic gain-of-function phenotype resulting in neurodegeneration. Numerous studies in recent years have provided evidence that defects in nucleocytoplasmic transport critically contribute to the pathology of these neurodegenerative diseases. A new mechanistic view is emerging, implicating three types of perturbations in normal cellular pathways that rely on nucleocytoplasmic transport: displacement of nuclear transport receptors and nucleoporins from nuclear pore complexes (NPCs), mislocalization and aggregation of RNA-binding proteins, and weakening of the chaperone activity of nuclear import receptors. MDPI 2018-11-26 /pmc/articles/PMC6316434/ /pubmed/30486313 http://dx.doi.org/10.3390/cells7120232 Text en © 2018 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Commentary
Fahrenkrog, Birthe
Harel, Amnon
Perturbations in Traffic: Aberrant Nucleocytoplasmic Transport at the Heart of Neurodegeneration
title Perturbations in Traffic: Aberrant Nucleocytoplasmic Transport at the Heart of Neurodegeneration
title_full Perturbations in Traffic: Aberrant Nucleocytoplasmic Transport at the Heart of Neurodegeneration
title_fullStr Perturbations in Traffic: Aberrant Nucleocytoplasmic Transport at the Heart of Neurodegeneration
title_full_unstemmed Perturbations in Traffic: Aberrant Nucleocytoplasmic Transport at the Heart of Neurodegeneration
title_short Perturbations in Traffic: Aberrant Nucleocytoplasmic Transport at the Heart of Neurodegeneration
title_sort perturbations in traffic: aberrant nucleocytoplasmic transport at the heart of neurodegeneration
topic Commentary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316434/
https://www.ncbi.nlm.nih.gov/pubmed/30486313
http://dx.doi.org/10.3390/cells7120232
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