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SC75741, A Novel c-Abl Inhibitor, Promotes the Clearance of TDP25 Aggregates via ATG5-Dependent Autophagy Pathway

Abnormal accumulation of TDP43-related mutant proteins in the cytoplasm causes amyotrophic lateral sclerosis (ALS). Herein, unbiased drug screening approaches showed that SC75741, a multi-target inhibitor, inhibited inflammation-induced aggregation by inhibiting NF-κB and also degraded already aggre...

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Autores principales: Zhou, Dongheng, Yan, Huanhuan, Yang, Shuying, Zhang, Yuhong, Xu, Xiaoyan, Cen, Xufeng, Lei, Kai, Xia, Hongguang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586708/
https://www.ncbi.nlm.nih.gov/pubmed/34776962
http://dx.doi.org/10.3389/fphar.2021.741219
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author Zhou, Dongheng
Yan, Huanhuan
Yang, Shuying
Zhang, Yuhong
Xu, Xiaoyan
Cen, Xufeng
Lei, Kai
Xia, Hongguang
author_facet Zhou, Dongheng
Yan, Huanhuan
Yang, Shuying
Zhang, Yuhong
Xu, Xiaoyan
Cen, Xufeng
Lei, Kai
Xia, Hongguang
author_sort Zhou, Dongheng
collection PubMed
description Abnormal accumulation of TDP43-related mutant proteins in the cytoplasm causes amyotrophic lateral sclerosis (ALS). Herein, unbiased drug screening approaches showed that SC75741, a multi-target inhibitor, inhibited inflammation-induced aggregation by inhibiting NF-κB and also degraded already aggregated proteins by inhibiting c-Abl mediated autophagy-lysosomal pathway. We delineate the mechanism that SC75741 could markedly enhance TFEB nuclear translocation by an mTORC1-independent TFEB regulatory pathway. In addition, SC75741 enhanced the interaction between p62 with TDP25 and LC3C, thus promoting TDP25 degradation. Taken together, these findings show that SC75741 has beneficial neuroprotective effects in ALS. Our study elucidates that dual-targeted inhibition of c-Abl and NF-κB may be a potential treatment for TDP43 proteinopathies and ALS.
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spelling pubmed-85867082021-11-13 SC75741, A Novel c-Abl Inhibitor, Promotes the Clearance of TDP25 Aggregates via ATG5-Dependent Autophagy Pathway Zhou, Dongheng Yan, Huanhuan Yang, Shuying Zhang, Yuhong Xu, Xiaoyan Cen, Xufeng Lei, Kai Xia, Hongguang Front Pharmacol Pharmacology Abnormal accumulation of TDP43-related mutant proteins in the cytoplasm causes amyotrophic lateral sclerosis (ALS). Herein, unbiased drug screening approaches showed that SC75741, a multi-target inhibitor, inhibited inflammation-induced aggregation by inhibiting NF-κB and also degraded already aggregated proteins by inhibiting c-Abl mediated autophagy-lysosomal pathway. We delineate the mechanism that SC75741 could markedly enhance TFEB nuclear translocation by an mTORC1-independent TFEB regulatory pathway. In addition, SC75741 enhanced the interaction between p62 with TDP25 and LC3C, thus promoting TDP25 degradation. Taken together, these findings show that SC75741 has beneficial neuroprotective effects in ALS. Our study elucidates that dual-targeted inhibition of c-Abl and NF-κB may be a potential treatment for TDP43 proteinopathies and ALS. Frontiers Media S.A. 2021-10-29 /pmc/articles/PMC8586708/ /pubmed/34776962 http://dx.doi.org/10.3389/fphar.2021.741219 Text en Copyright © 2021 Zhou, Yan, Yang, Zhang, Xu, Cen, Lei and Xia. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Zhou, Dongheng
Yan, Huanhuan
Yang, Shuying
Zhang, Yuhong
Xu, Xiaoyan
Cen, Xufeng
Lei, Kai
Xia, Hongguang
SC75741, A Novel c-Abl Inhibitor, Promotes the Clearance of TDP25 Aggregates via ATG5-Dependent Autophagy Pathway
title SC75741, A Novel c-Abl Inhibitor, Promotes the Clearance of TDP25 Aggregates via ATG5-Dependent Autophagy Pathway
title_full SC75741, A Novel c-Abl Inhibitor, Promotes the Clearance of TDP25 Aggregates via ATG5-Dependent Autophagy Pathway
title_fullStr SC75741, A Novel c-Abl Inhibitor, Promotes the Clearance of TDP25 Aggregates via ATG5-Dependent Autophagy Pathway
title_full_unstemmed SC75741, A Novel c-Abl Inhibitor, Promotes the Clearance of TDP25 Aggregates via ATG5-Dependent Autophagy Pathway
title_short SC75741, A Novel c-Abl Inhibitor, Promotes the Clearance of TDP25 Aggregates via ATG5-Dependent Autophagy Pathway
title_sort sc75741, a novel c-abl inhibitor, promotes the clearance of tdp25 aggregates via atg5-dependent autophagy pathway
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586708/
https://www.ncbi.nlm.nih.gov/pubmed/34776962
http://dx.doi.org/10.3389/fphar.2021.741219
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