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c-Abl Regulates the Pathological Deposition of TDP-43 via Tyrosine 43 Phosphorylation
Non-receptor tyrosine kinase, c-Abl plays a role in the pathogenesis of several neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Here, we found that TDP-43, which was one of the main proteins comprising pathological deposits in amyotrophic lateral sclerosis (ALS), is...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9776721/ https://www.ncbi.nlm.nih.gov/pubmed/36552734 http://dx.doi.org/10.3390/cells11243972 |
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author | Lee, Saebom Ryu, Hye Guk Kweon, Sin Ho Kim, Hyerynn Park, Hyeonwoo Lee, Kyung-Ha Jang, Sang-Min Na, Chan Hyun Kim, Sangjune Ko, Han Seok |
author_facet | Lee, Saebom Ryu, Hye Guk Kweon, Sin Ho Kim, Hyerynn Park, Hyeonwoo Lee, Kyung-Ha Jang, Sang-Min Na, Chan Hyun Kim, Sangjune Ko, Han Seok |
author_sort | Lee, Saebom |
collection | PubMed |
description | Non-receptor tyrosine kinase, c-Abl plays a role in the pathogenesis of several neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Here, we found that TDP-43, which was one of the main proteins comprising pathological deposits in amyotrophic lateral sclerosis (ALS), is a novel substrate for c-Abl. The phosphorylation of tyrosine 43 of TDP-43 by c-Abl led to increased TDP-43 levels in the cytoplasm and increased the formation of G3BP1-positive stress granules in SH-SY5Y cells. The kinase-dead mutant of c-Abl had no effect on the cytoplasmic localization of TDP-43. The expression of phosphor-mimetic mutant Y43E of TDP-43 in primary cortical neurons accumulated the neurite granule. Furthermore, the phosphorylation of TDP-43 at tyrosine 43 by c-Abl promoted the aggregation of TDP-43 and increased neuronal cell death in primary cortical neurons, but not in c-Abl–deficient primary cortical neurons. Identification of c-Abl as the kinase of TDP43 provides new insight into the pathogenesis of ALS. |
format | Online Article Text |
id | pubmed-9776721 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-97767212022-12-23 c-Abl Regulates the Pathological Deposition of TDP-43 via Tyrosine 43 Phosphorylation Lee, Saebom Ryu, Hye Guk Kweon, Sin Ho Kim, Hyerynn Park, Hyeonwoo Lee, Kyung-Ha Jang, Sang-Min Na, Chan Hyun Kim, Sangjune Ko, Han Seok Cells Article Non-receptor tyrosine kinase, c-Abl plays a role in the pathogenesis of several neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Here, we found that TDP-43, which was one of the main proteins comprising pathological deposits in amyotrophic lateral sclerosis (ALS), is a novel substrate for c-Abl. The phosphorylation of tyrosine 43 of TDP-43 by c-Abl led to increased TDP-43 levels in the cytoplasm and increased the formation of G3BP1-positive stress granules in SH-SY5Y cells. The kinase-dead mutant of c-Abl had no effect on the cytoplasmic localization of TDP-43. The expression of phosphor-mimetic mutant Y43E of TDP-43 in primary cortical neurons accumulated the neurite granule. Furthermore, the phosphorylation of TDP-43 at tyrosine 43 by c-Abl promoted the aggregation of TDP-43 and increased neuronal cell death in primary cortical neurons, but not in c-Abl–deficient primary cortical neurons. Identification of c-Abl as the kinase of TDP43 provides new insight into the pathogenesis of ALS. MDPI 2022-12-08 /pmc/articles/PMC9776721/ /pubmed/36552734 http://dx.doi.org/10.3390/cells11243972 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 | Article Lee, Saebom Ryu, Hye Guk Kweon, Sin Ho Kim, Hyerynn Park, Hyeonwoo Lee, Kyung-Ha Jang, Sang-Min Na, Chan Hyun Kim, Sangjune Ko, Han Seok c-Abl Regulates the Pathological Deposition of TDP-43 via Tyrosine 43 Phosphorylation |
title | c-Abl Regulates the Pathological Deposition of TDP-43 via Tyrosine 43 Phosphorylation |
title_full | c-Abl Regulates the Pathological Deposition of TDP-43 via Tyrosine 43 Phosphorylation |
title_fullStr | c-Abl Regulates the Pathological Deposition of TDP-43 via Tyrosine 43 Phosphorylation |
title_full_unstemmed | c-Abl Regulates the Pathological Deposition of TDP-43 via Tyrosine 43 Phosphorylation |
title_short | c-Abl Regulates the Pathological Deposition of TDP-43 via Tyrosine 43 Phosphorylation |
title_sort | c-abl regulates the pathological deposition of tdp-43 via tyrosine 43 phosphorylation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9776721/ https://www.ncbi.nlm.nih.gov/pubmed/36552734 http://dx.doi.org/10.3390/cells11243972 |
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