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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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