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:	Shinrye Lee, Myungjin Jo, Hye Eun Lee, Yu-Mi Jeon, Seyeon Kim, Younghwi Kwon, Junghwa Woo, Shin Han, Ji Young Mun, Hyung-Jun Kim
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	catechol autophagy mitochondrial dysfunction TDP-43 ALS Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/6305d0d3ae16481486bbb38daf985c2a
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spelling	oai:doaj.org-article:6305d0d3ae16481486bbb38daf985c2a2021-12-02T10:58:31ZHEXA-018, a Novel Inducer of Autophagy, Rescues TDP-43 Toxicity in Neuronal Cells1663-981210.3389/fphar.2021.747975https://doaj.org/article/6305d0d3ae16481486bbb38daf985c2a2021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.747975/fullhttps://doaj.org/toc/1663-9812The 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.Shinrye LeeMyungjin JoHye Eun LeeYu-Mi JeonSeyeon KimSeyeon KimYounghwi KwonYounghwi KwonJunghwa WooShin HanJi Young MunHyung-Jun KimFrontiers Media S.A.articlecatecholautophagymitochondrial dysfunctionTDP-43ALSTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	catechol autophagy mitochondrial dysfunction TDP-43 ALS Therapeutics. Pharmacology RM1-950
spellingShingle	catechol autophagy mitochondrial dysfunction TDP-43 ALS Therapeutics. Pharmacology RM1-950 Shinrye Lee Myungjin Jo Hye Eun Lee Yu-Mi Jeon Seyeon Kim Seyeon Kim Younghwi Kwon Younghwi Kwon Junghwa Woo Shin Han Ji Young Mun Hyung-Jun Kim HEXA-018, a Novel Inducer of Autophagy, Rescues TDP-43 Toxicity in Neuronal Cells
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.
format	article
author	Shinrye Lee Myungjin Jo Hye Eun Lee Yu-Mi Jeon Seyeon Kim Seyeon Kim Younghwi Kwon Younghwi Kwon Junghwa Woo Shin Han Ji Young Mun Hyung-Jun Kim
author_facet	Shinrye Lee Myungjin Jo Hye Eun Lee Yu-Mi Jeon Seyeon Kim Seyeon Kim Younghwi Kwon Younghwi Kwon Junghwa Woo Shin Han Ji Young Mun Hyung-Jun Kim
author_sort	Shinrye Lee
title	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_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_sort	hexa-018, a novel inducer of autophagy, rescues tdp-43 toxicity in neuronal cells
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/6305d0d3ae16481486bbb38daf985c2a
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HEXA-018, a Novel Inducer of Autophagy, Rescues TDP-43 Toxicity in Neuronal Cells

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