Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Liu, Guangbo, Coyne, Alyssa N., Pei, Fen, Vaughan, Spencer, Chaung, Matthew, Zarnescu, Daniela C., Buchan, J. Ross
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
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
_version_ 1783285795420897280
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
work_keys_str_mv AT liuguangbo endocytosisregulatestdp43toxicityandturnover
AT coynealyssan endocytosisregulatestdp43toxicityandturnover
AT peifen endocytosisregulatestdp43toxicityandturnover
AT vaughanspencer endocytosisregulatestdp43toxicityandturnover
AT chaungmatthew endocytosisregulatestdp43toxicityandturnover
AT zarnescudanielac endocytosisregulatestdp43toxicityandturnover
AT buchanjross endocytosisregulatestdp43toxicityandturnover