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Endocytosis regulates TDP-43 toxicity and turnover
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. ALS-affected motor neurons exhibit aberrant localization of a nuclear RNA binding protein, TDP-43, into cytoplasmic aggregates, which contributes to pathology via unclear mechanisms. Here, we demonstrate that TDP-43 tu...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727062/ https://www.ncbi.nlm.nih.gov/pubmed/29233983 http://dx.doi.org/10.1038/s41467-017-02017-x |
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author | Liu, Guangbo Coyne, Alyssa N. Pei, Fen Vaughan, Spencer Chaung, Matthew Zarnescu, Daniela C. Buchan, J. Ross |
author_facet | Liu, Guangbo Coyne, Alyssa N. Pei, Fen Vaughan, Spencer Chaung, Matthew Zarnescu, Daniela C. Buchan, J. Ross |
author_sort | Liu, Guangbo |
collection | PubMed |
description | Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. ALS-affected motor neurons exhibit aberrant localization of a nuclear RNA binding protein, TDP-43, into cytoplasmic aggregates, which contributes to pathology via unclear mechanisms. Here, we demonstrate that TDP-43 turnover and toxicity depend in part upon the endocytosis pathway. TDP-43 inhibits endocytosis, and co-localizes strongly with endocytic proteins, including in ALS patient tissue. Impairing endocytosis increases TDP-43 toxicity, aggregation, and protein levels, whereas enhancing endocytosis reverses these phenotypes. Locomotor dysfunction in a TDP-43 ALS fly model is also exacerbated and suppressed by impairment and enhancement of endocytic function, respectively. Thus, endocytosis dysfunction may be an underlying cause of ALS pathology. |
format | Online Article Text |
id | pubmed-5727062 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-57270622017-12-14 Endocytosis regulates TDP-43 toxicity and turnover Liu, Guangbo Coyne, Alyssa N. Pei, Fen Vaughan, Spencer Chaung, Matthew Zarnescu, Daniela C. Buchan, J. Ross Nat Commun Article Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. ALS-affected motor neurons exhibit aberrant localization of a nuclear RNA binding protein, TDP-43, into cytoplasmic aggregates, which contributes to pathology via unclear mechanisms. Here, we demonstrate that TDP-43 turnover and toxicity depend in part upon the endocytosis pathway. TDP-43 inhibits endocytosis, and co-localizes strongly with endocytic proteins, including in ALS patient tissue. Impairing endocytosis increases TDP-43 toxicity, aggregation, and protein levels, whereas enhancing endocytosis reverses these phenotypes. Locomotor dysfunction in a TDP-43 ALS fly model is also exacerbated and suppressed by impairment and enhancement of endocytic function, respectively. Thus, endocytosis dysfunction may be an underlying cause of ALS pathology. Nature Publishing Group UK 2017-12-12 /pmc/articles/PMC5727062/ /pubmed/29233983 http://dx.doi.org/10.1038/s41467-017-02017-x Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Liu, Guangbo Coyne, Alyssa N. Pei, Fen Vaughan, Spencer Chaung, Matthew Zarnescu, Daniela C. Buchan, J. Ross Endocytosis regulates TDP-43 toxicity and turnover |
title | Endocytosis regulates TDP-43 toxicity and turnover |
title_full | Endocytosis regulates TDP-43 toxicity and turnover |
title_fullStr | Endocytosis regulates TDP-43 toxicity and turnover |
title_full_unstemmed | Endocytosis regulates TDP-43 toxicity and turnover |
title_short | Endocytosis regulates TDP-43 toxicity and turnover |
title_sort | endocytosis regulates tdp-43 toxicity and turnover |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727062/ https://www.ncbi.nlm.nih.gov/pubmed/29233983 http://dx.doi.org/10.1038/s41467-017-02017-x |
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