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Small-molecule activators of NRF1 transcriptional activity prevent protein aggregaton

dc.contributor.authorSedláček, Jindřich
dc.contributor.authorŠmahelová, Zuzana
dc.contributor.authorAdámek, Michael
dc.contributor.authorŠubová, Dominika
dc.contributor.authorMajer, Pavel
dc.contributor.authorSvobodová, Lucie
dc.contributor.authorKadlecová, Alena
dc.contributor.authorPetrezsélyová, Silvia
dc.contributor.authorMachara, Aleš
dc.contributor.authorGrantz Šašková, Klára
dc.date.accessioned2024-10-14T09:15:45Z
dc.date.available2024-10-14T09:15:45Z
dc.date.issued2024
dc.identifier.urihttps://hdl.handle.net/20.500.14178/2654
dc.description.abstractIntracellular protein aggregation causes proteotoxic stress, underlying highly debilitating neurodegenerative disorders in parallel with decreased proteasome activity.Nevertheless, under such stress conditions, the expression of proteasome subunits is upregulated by Nuclear Factor Erythroid 2 2-related factor 1 (NRF1), a transcription factor that is encoded by NFE2L1 . Activating the NRF1 pathway could accordingly delay the onset of neurodegenerative and other disorders with impaired cell proteostasis. Here, we present a series of small small-molecule compounds based on bis (phenylmethylen)cycloalkanones and their heterocyclic analogues, identified via targeted library screening, that can induce NRF1 NRF1-dependent downstream events, such as proteasome synthesis, heat shock response, and autophagy, in both model cell lines and Caenorhabditis elegans strains.These compounds increase proteasome activity and decrease the size and number of protein aggregates without causing any cellular stress or inhibiting the ubiquitin ubiquitin-proteasome system (UPS). Therefore, our compounds represent a new promising therapeutic approach to various protein conformational diseases, including the most debilitating neurodegenerative diseases and viral diseases.en
dc.language.isoen
dc.publisherČeská společnost chemická
dc.relation.urlhttps://nivb.cz/2024/09/24/nivb-meeting-2024-treti-vyrocni-setkani-narodniho-ustavu-virologie-a-bakteriologie/
dc.rightsCreative Commons Uveďte původ 4.0 Internationalcs
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.titleSmall-molecule activators of NRF1 transcriptional activity prevent protein aggregatonen
dcterms.accessRightsopenAccess
dcterms.licensehttps://creativecommons.org/licenses/by/4.0/legalcode
dc.date.updated2024-10-14T09:15:45Z
dc.subject.keywordNRF1en
dc.subject.keywordproteinen
dc.identifier.eissn2336-7210
dc.relation.fundingReferenceinfo:eu-repo/grantAgreement/MSM//LX22NPO5103
dc.date.embargoStartDate2024-10-14
dc.type.obd110
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dc.identifier.obd653750
dc.subject.rivPrimary10000::10600
dcterms.isPartOf.nameCzech Chemical Society Symposium Series
dcterms.isPartOf.issn2336-7202
dcterms.isPartOf.journalYear2024
dcterms.isPartOf.journalVolume22
dcterms.isPartOf.journalIssue6
uk.faculty.primaryId115
uk.faculty.primaryNamePřírodovědecká fakultacs
uk.faculty.primaryNameFaculty of Scienceen
uk.department.primaryId1034
uk.department.primaryNameKatedra genetiky a mikrobiologiecs
uk.department.primaryNameDepartment of Genetics and Microbiologyen
uk.department.secondaryId1035
uk.department.secondaryNameKatedra buněčné biologiecs
uk.department.secondaryNameDepartment of Cell Biologyen
uk.event.nameThe third annual meeting of the National Institute of Virology and Bacterology (NIVB)
dc.description.pageRange250-250
dc.type.obdHierarchyCsABSTRAKT::abstrakt::abstrakt v elektronické podoběcs
dc.type.obdHierarchyEnABSTRACT::abstract::abstract in e-formen
dc.type.obdHierarchyCode110::130::136en
uk.displayTitleSmall-molecule activators of NRF1 transcriptional activity prevent protein aggregatonen


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