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Article: AQAMAN, a bisamidine-based inhibitor of toxic protein inclusions in neurons, ameliorates cytotoxicity in polyglutamine disease models

TitleAQAMAN, a bisamidine-based inhibitor of toxic protein inclusions in neurons, ameliorates cytotoxicity in polyglutamine disease models
Authors
Issue Date2019
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal of Biological Chemistry, 2019, v. 294 n. 8, p. 2757-2770 How to Cite?
AbstractPolyglutamine (polyQ) diseases are a group of dominantly inherited neurodegenerative disorders caused by the expansion of an unstable CAG repeat in the coding region of the affected genes. Hallmarks of polyQ diseases include the accumulation of misfolded protein aggregates, leading to neuronal degeneration and cell death. PolyQ diseases are currently incurable, highlighting the urgent need for approaches that inhibit the formation of disaggregate cytotoxic polyQ protein inclusions. Here, we screened for bisamidine-based inhibitors that can inhibit neuronal polyQ protein inclusions. We demonstrated that one inhibitor, AQAMAN, prevents polyQ protein aggregation and promotes de-aggregation of self-assembled polyQ proteins in several models of polyQ diseases. Using immunocytochemistry, we found that AQAMAN significantly reduces polyQ protein aggregation and specifically suppresses polyQ protein–induced cell death. Using a recombinant and purified polyQ protein (thioredoxin–Huntingtin–Q46), we further demonstrated that AQAMAN interferes with polyQ self-assembly, preventing polyQ aggregation, and dissociates preformed polyQ aggregates in a cell-free system. Remarkably, AQAMAN feeding of Drosophila expressing expanded polyQ disease protein suppresses polyQ-induced neurodegeneration in vivo. In addition, using inhibitors and activators of the autophagy pathway, we demonstrated that AQAMAN's cytoprotective effect against polyQ toxicity is autophagy-dependent. In summary, we have identified AQAMAN as a potential therapeutic for combating polyQ protein toxicity in polyQ diseases. Our findings further highlight the importance of the autophagy pathway in clearing harmful polyQ proteins.
Persistent Identifierhttp://hdl.handle.net/10722/268167
ISSN
2020 Impact Factor: 5.157
2023 SCImago Journal Rankings: 1.766
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHong, H-
dc.contributor.authorKoon, AC-
dc.contributor.authorChen, ZS-
dc.contributor.authorWei, Y-
dc.contributor.authorAn, Y-
dc.contributor.authorLi, W-
dc.contributor.authorLau, MHY-
dc.contributor.authorLau, KF-
dc.contributor.authorNgo, JCK-
dc.contributor.authorWong, CH-
dc.contributor.authorAu-Yeung, HY-
dc.contributor.authorZimmerman, SC-
dc.contributor.authorChan, HYE-
dc.date.accessioned2019-03-18T04:19:56Z-
dc.date.available2019-03-18T04:19:56Z-
dc.date.issued2019-
dc.identifier.citationJournal of Biological Chemistry, 2019, v. 294 n. 8, p. 2757-2770-
dc.identifier.issn0021-9258-
dc.identifier.urihttp://hdl.handle.net/10722/268167-
dc.description.abstractPolyglutamine (polyQ) diseases are a group of dominantly inherited neurodegenerative disorders caused by the expansion of an unstable CAG repeat in the coding region of the affected genes. Hallmarks of polyQ diseases include the accumulation of misfolded protein aggregates, leading to neuronal degeneration and cell death. PolyQ diseases are currently incurable, highlighting the urgent need for approaches that inhibit the formation of disaggregate cytotoxic polyQ protein inclusions. Here, we screened for bisamidine-based inhibitors that can inhibit neuronal polyQ protein inclusions. We demonstrated that one inhibitor, AQAMAN, prevents polyQ protein aggregation and promotes de-aggregation of self-assembled polyQ proteins in several models of polyQ diseases. Using immunocytochemistry, we found that AQAMAN significantly reduces polyQ protein aggregation and specifically suppresses polyQ protein–induced cell death. Using a recombinant and purified polyQ protein (thioredoxin–Huntingtin–Q46), we further demonstrated that AQAMAN interferes with polyQ self-assembly, preventing polyQ aggregation, and dissociates preformed polyQ aggregates in a cell-free system. Remarkably, AQAMAN feeding of Drosophila expressing expanded polyQ disease protein suppresses polyQ-induced neurodegeneration in vivo. In addition, using inhibitors and activators of the autophagy pathway, we demonstrated that AQAMAN's cytoprotective effect against polyQ toxicity is autophagy-dependent. In summary, we have identified AQAMAN as a potential therapeutic for combating polyQ protein toxicity in polyQ diseases. Our findings further highlight the importance of the autophagy pathway in clearing harmful polyQ proteins.-
dc.languageeng-
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/-
dc.relation.ispartofJournal of Biological Chemistry-
dc.rightsThis research was originally published in the Journal of Biological Chemistry. Huiling Hong, Alex Chun Koon, Zhefan Stephen Chen, et al. AQAMAN, a bisamidine-based inhibitor of toxic protein inclusions in neurons, ameliorates cytotoxicity in polyglutamine disease models. J Biol Chem. 2019; 294:2757-2770. © the Author(s).-
dc.titleAQAMAN, a bisamidine-based inhibitor of toxic protein inclusions in neurons, ameliorates cytotoxicity in polyglutamine disease models-
dc.typeArticle-
dc.identifier.emailAu Yeung, HY: hoyuay@hku.hk-
dc.identifier.authorityAu Yeung, HY=rp01819-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1074/jbc.RA118.006307-
dc.identifier.pmid30593503-
dc.identifier.pmcidPMC6393596-
dc.identifier.scopuseid_2-s2.0-85062022452-
dc.identifier.hkuros297245-
dc.identifier.volume294-
dc.identifier.issue8-
dc.identifier.spage2757-
dc.identifier.epage2770-
dc.identifier.isiWOS:000459601600016-
dc.publisher.placeUnited States-
dc.identifier.issnl0021-9258-

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