Cargando…
Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis
The transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological protein of amyotrophic lateral sclerosis (ALS). TDP-43 pathology is characterized by a combination of the cytoplasmic aggregation and nuclear clearance of this protein. However, the mechanisms underlying TDP-43 patholo...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418808/ https://www.ncbi.nlm.nih.gov/pubmed/37569549 http://dx.doi.org/10.3390/ijms241512176 |
_version_ | 1785088355714727936 |
---|---|
author | Yabata, Hiroyuki Riku, Yuichi Miyahara, Hiroaki Akagi, Akio Sone, Jun Urushitani, Makoto Yoshida, Mari Iwasaki, Yasushi |
author_facet | Yabata, Hiroyuki Riku, Yuichi Miyahara, Hiroaki Akagi, Akio Sone, Jun Urushitani, Makoto Yoshida, Mari Iwasaki, Yasushi |
author_sort | Yabata, Hiroyuki |
collection | PubMed |
description | The transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological protein of amyotrophic lateral sclerosis (ALS). TDP-43 pathology is characterized by a combination of the cytoplasmic aggregation and nuclear clearance of this protein. However, the mechanisms underlying TDP-43 pathology have not been fully clarified. The aim of this study was to evaluate the relationships between the expression level of nuclear TDP-43 and the pathological properties of cytoplasmic aggregates in autopsied ALS cases. We included 22 consecutively autopsied cases with sporadic TDP-43-related ALS. The motor neuron systems were neuropathologically assessed. We identified 790 neurons with cytoplasmic TDP-43 inclusions from the lower motor neuron system of included cases. Nuclear TDP-43 disappeared in 84% (n = 660) and expressed in 16% (n = 130) of neurons with cytoplasmic inclusions; the former was defined as TDP-43 cytoplasmic immunoreactivity (c-ir), and the latter was defined as nuclear and cytoplasmic immunoreactivity (n/c-ir). Morphologically, diffuse cytoplasmic inclusions were significantly more prevalent in TDP-43 n/c-ir neurons than in c-ir neurons, while skein-like and round inclusions were less prevalent in n/c-ir neurons. The cytoplasmic inclusions of TDP-43 n/c-ir neurons were phosphorylated but poorly ubiquitylated when compared with those of c-ir neurons. TDP-43 n/c-ir neurons became less dominant than the c-ir neurons among cases with a prolonged disease duration. The expression level of nuclear TDP-43 was significantly lower in n/c-ir neurons than in normal neurons without cytoplasmic inclusions. Our results indicate that the maturation of cytoplasmic TDP-43 inclusions correlates with the depletion of nuclear TDP-43 in each affected neuron. This finding supports the view that an imbalance between nuclear and cytoplasmic TDP-43 may be an essential pathway to TDP-43 pathology. |
format | Online Article Text |
id | pubmed-10418808 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-104188082023-08-12 Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis Yabata, Hiroyuki Riku, Yuichi Miyahara, Hiroaki Akagi, Akio Sone, Jun Urushitani, Makoto Yoshida, Mari Iwasaki, Yasushi Int J Mol Sci Article The transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological protein of amyotrophic lateral sclerosis (ALS). TDP-43 pathology is characterized by a combination of the cytoplasmic aggregation and nuclear clearance of this protein. However, the mechanisms underlying TDP-43 pathology have not been fully clarified. The aim of this study was to evaluate the relationships between the expression level of nuclear TDP-43 and the pathological properties of cytoplasmic aggregates in autopsied ALS cases. We included 22 consecutively autopsied cases with sporadic TDP-43-related ALS. The motor neuron systems were neuropathologically assessed. We identified 790 neurons with cytoplasmic TDP-43 inclusions from the lower motor neuron system of included cases. Nuclear TDP-43 disappeared in 84% (n = 660) and expressed in 16% (n = 130) of neurons with cytoplasmic inclusions; the former was defined as TDP-43 cytoplasmic immunoreactivity (c-ir), and the latter was defined as nuclear and cytoplasmic immunoreactivity (n/c-ir). Morphologically, diffuse cytoplasmic inclusions were significantly more prevalent in TDP-43 n/c-ir neurons than in c-ir neurons, while skein-like and round inclusions were less prevalent in n/c-ir neurons. The cytoplasmic inclusions of TDP-43 n/c-ir neurons were phosphorylated but poorly ubiquitylated when compared with those of c-ir neurons. TDP-43 n/c-ir neurons became less dominant than the c-ir neurons among cases with a prolonged disease duration. The expression level of nuclear TDP-43 was significantly lower in n/c-ir neurons than in normal neurons without cytoplasmic inclusions. Our results indicate that the maturation of cytoplasmic TDP-43 inclusions correlates with the depletion of nuclear TDP-43 in each affected neuron. This finding supports the view that an imbalance between nuclear and cytoplasmic TDP-43 may be an essential pathway to TDP-43 pathology. MDPI 2023-07-29 /pmc/articles/PMC10418808/ /pubmed/37569549 http://dx.doi.org/10.3390/ijms241512176 Text en © 2023 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 | Article Yabata, Hiroyuki Riku, Yuichi Miyahara, Hiroaki Akagi, Akio Sone, Jun Urushitani, Makoto Yoshida, Mari Iwasaki, Yasushi Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis |
title | Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis |
title_full | Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis |
title_fullStr | Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis |
title_full_unstemmed | Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis |
title_short | Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis |
title_sort | nuclear expression of tdp-43 is linked with morphology and ubiquitylation of cytoplasmic aggregates in amyotrophic lateral sclerosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418808/ https://www.ncbi.nlm.nih.gov/pubmed/37569549 http://dx.doi.org/10.3390/ijms241512176 |
work_keys_str_mv | AT yabatahiroyuki nuclearexpressionoftdp43islinkedwithmorphologyandubiquitylationofcytoplasmicaggregatesinamyotrophiclateralsclerosis AT rikuyuichi nuclearexpressionoftdp43islinkedwithmorphologyandubiquitylationofcytoplasmicaggregatesinamyotrophiclateralsclerosis AT miyaharahiroaki nuclearexpressionoftdp43islinkedwithmorphologyandubiquitylationofcytoplasmicaggregatesinamyotrophiclateralsclerosis AT akagiakio nuclearexpressionoftdp43islinkedwithmorphologyandubiquitylationofcytoplasmicaggregatesinamyotrophiclateralsclerosis AT sonejun nuclearexpressionoftdp43islinkedwithmorphologyandubiquitylationofcytoplasmicaggregatesinamyotrophiclateralsclerosis AT urushitanimakoto nuclearexpressionoftdp43islinkedwithmorphologyandubiquitylationofcytoplasmicaggregatesinamyotrophiclateralsclerosis AT yoshidamari nuclearexpressionoftdp43islinkedwithmorphologyandubiquitylationofcytoplasmicaggregatesinamyotrophiclateralsclerosis AT iwasakiyasushi nuclearexpressionoftdp43islinkedwithmorphologyandubiquitylationofcytoplasmicaggregatesinamyotrophiclateralsclerosis |