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HEXA-018, a Novel Inducer of Autophagy, Rescues TDP-43 Toxicity in Neuronal Cells

The autophagy-lysosomal pathway is an essential cellular mechanism that degrades aggregated proteins and damaged cellular components to maintain cellular homeostasis. Here, we identified HEXA-018, a novel compound containing a catechol derivative structure, as a novel inducer of autophagy. HEXA-018...

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Autores principales: Lee, Shinrye, Jo, Myungjin, Lee, Hye Eun, Jeon, Yu-Mi, Kim, Seyeon, Kwon, Younghwi, Woo, Junghwa, Han, Shin, Mun, Ji Young, Kim, Hyung-Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8675103/
https://www.ncbi.nlm.nih.gov/pubmed/34925009
http://dx.doi.org/10.3389/fphar.2021.747975
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author Lee, Shinrye
Jo, Myungjin
Lee, Hye Eun
Jeon, Yu-Mi
Kim, Seyeon
Kwon, Younghwi
Woo, Junghwa
Han, Shin
Mun, Ji Young
Kim, Hyung-Jun
author_facet Lee, Shinrye
Jo, Myungjin
Lee, Hye Eun
Jeon, Yu-Mi
Kim, Seyeon
Kwon, Younghwi
Woo, Junghwa
Han, Shin
Mun, Ji Young
Kim, Hyung-Jun
author_sort Lee, Shinrye
collection PubMed
description The autophagy-lysosomal pathway is an essential cellular mechanism that degrades aggregated proteins and damaged cellular components to maintain cellular homeostasis. Here, we identified HEXA-018, a novel compound containing a catechol derivative structure, as a novel inducer of autophagy. HEXA-018 increased the LC3-I/II ratio, which indicates activation of autophagy. Consistent with this result, HEXA-018 effectively increased the numbers of autophagosomes and autolysosomes in neuronal cells. We also found that the activation of autophagy by HEXA-018 is mediated by the AMPK-ULK1 pathway in an mTOR-independent manner. We further showed that ubiquitin proteasome system impairment- or oxidative stress-induced neurotoxicity was significantly reduced by HEXA-018 treatment. Moreover, oxidative stress-induced mitochondrial dysfunction was strongly ameliorated by HEXA-018 treatment. In addition, we investigated the efficacy of HEXA-018 in models of TDP-43 proteinopathy. HEXA-018 treatment mitigated TDP-43 toxicity in cultured neuronal cell lines and Drosophila. Our data indicate that HEXA-018 could be a new drug candidate for TDP-43-associated neurodegenerative diseases.
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spelling pubmed-86751032021-12-17 HEXA-018, a Novel Inducer of Autophagy, Rescues TDP-43 Toxicity in Neuronal Cells Lee, Shinrye Jo, Myungjin Lee, Hye Eun Jeon, Yu-Mi Kim, Seyeon Kwon, Younghwi Woo, Junghwa Han, Shin Mun, Ji Young Kim, Hyung-Jun Front Pharmacol Pharmacology The autophagy-lysosomal pathway is an essential cellular mechanism that degrades aggregated proteins and damaged cellular components to maintain cellular homeostasis. Here, we identified HEXA-018, a novel compound containing a catechol derivative structure, as a novel inducer of autophagy. HEXA-018 increased the LC3-I/II ratio, which indicates activation of autophagy. Consistent with this result, HEXA-018 effectively increased the numbers of autophagosomes and autolysosomes in neuronal cells. We also found that the activation of autophagy by HEXA-018 is mediated by the AMPK-ULK1 pathway in an mTOR-independent manner. We further showed that ubiquitin proteasome system impairment- or oxidative stress-induced neurotoxicity was significantly reduced by HEXA-018 treatment. Moreover, oxidative stress-induced mitochondrial dysfunction was strongly ameliorated by HEXA-018 treatment. In addition, we investigated the efficacy of HEXA-018 in models of TDP-43 proteinopathy. HEXA-018 treatment mitigated TDP-43 toxicity in cultured neuronal cell lines and Drosophila. Our data indicate that HEXA-018 could be a new drug candidate for TDP-43-associated neurodegenerative diseases. Frontiers Media S.A. 2021-12-02 /pmc/articles/PMC8675103/ /pubmed/34925009 http://dx.doi.org/10.3389/fphar.2021.747975 Text en Copyright © 2021 Lee, Jo, Lee, Jeon, Kim, Kwon, Woo, Han, Mun and Kim. 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
Lee, Shinrye
Jo, Myungjin
Lee, Hye Eun
Jeon, Yu-Mi
Kim, Seyeon
Kwon, Younghwi
Woo, Junghwa
Han, Shin
Mun, Ji Young
Kim, Hyung-Jun
HEXA-018, a Novel Inducer of Autophagy, Rescues TDP-43 Toxicity in Neuronal Cells
title HEXA-018, a Novel Inducer of Autophagy, Rescues TDP-43 Toxicity in Neuronal Cells
title_full HEXA-018, a Novel Inducer of Autophagy, Rescues TDP-43 Toxicity in Neuronal Cells
title_fullStr HEXA-018, a Novel Inducer of Autophagy, Rescues TDP-43 Toxicity in Neuronal Cells
title_full_unstemmed HEXA-018, a Novel Inducer of Autophagy, Rescues TDP-43 Toxicity in Neuronal Cells
title_short HEXA-018, a Novel Inducer of Autophagy, Rescues TDP-43 Toxicity in Neuronal Cells
title_sort hexa-018, a novel inducer of autophagy, rescues tdp-43 toxicity in neuronal cells
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8675103/
https://www.ncbi.nlm.nih.gov/pubmed/34925009
http://dx.doi.org/10.3389/fphar.2021.747975
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