Small-molecule activators of NRF1 transcriptional activity prevent protein aggregaton
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11310%2F24%3A10486087" target="_blank" >RIV/00216208:11310/24:10486087 - isvavai.cz</a>
Result on the web
<a href="https://nivb.cz/2024/09/24/nivb-meeting-2024-treti-vyrocni-setkani-narodniho-ustavu-virologie-a-bakteriologie/" target="_blank" >https://nivb.cz/2024/09/24/nivb-meeting-2024-treti-vyrocni-setkani-narodniho-ustavu-virologie-a-bakteriologie/</a>
DOI - Digital Object Identifier
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Alternative languages
Result language
angličtina
Original language name
Small-molecule activators of NRF1 transcriptional activity prevent protein aggregaton
Original language description
Intracellular 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.
Czech name
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Czech description
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Classification
Type
O - Miscellaneous
CEP classification
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OECD FORD branch
10600 - Biological sciences
Result continuities
Project
<a href="/en/project/LX22NPO5103" target="_blank" >LX22NPO5103: National Institute of Virology and Bacteriology</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů